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Wai AP, Richardo T, Wakae K, Okada S, Muramatsu M, Yoshiyama H, Iizasa H. Persistent Epstein-Barr Virus Infection of Epithelial Cells Leads to APOBEC3C Expression and Induces Mitochondrial DNA Mutations. Microbiol Immunol 2025; 69:157-167. [PMID: 39704315 DOI: 10.1111/1348-0421.13196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 12/21/2024]
Abstract
Upon infection with the virus, cells increase the expression of cytidine deaminase APOBEC3 family genes. This leads to the accumulation of C-to-T mutations in the replicating viral genome and suppresses viral propagation. In contrast, herpesviruses, including Epstein-Barr virus (EBV), express genes that counteract APOBEC3 during lytic infection. However, because viral resistance factors are not expressed during EBV latent infection, it is unknown how APOBEC3 functions during latent infection. We observed that in gastric epithelial cells persistently infected with EBV, the expression of APOBEC3 family genes increased, C-to-T mutations in the D-loop genome of mitochondrial DNA (mtDNA) increased, and mtDNA copy number decreased. By introducing and expressing individual APOBEC3 family genes, APOBEC3C was particularly expressed in the cytoplasm, increasing C-to-T mutations in mtDNA and decreasing mtDNA copy number. Furthermore, we confirmed that APOBEC3C co-localized with mitochondria in EBV-infected cells. Expression of the EBV latent gene LMP2A increased APOBEC3C expression. Conversely, APOBEC3C expression was reduced in LMP2A-deficient EBV-infected cells compared to wild-type EBV-infected cells. These results indicate that persistent infection of EBV in gastric epithelial cells reduces the number of mitochondria through mtDNA mutations induced by APOBEC3C expression.
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Affiliation(s)
- Aung Phyo Wai
- Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Timmy Richardo
- Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
- Institute of Immunology, Department of Innate Immunity, University of Tübingen, Tübingen, Germany
| | - Kousho Wakae
- Department of Virology II, National Institute of Infectious Disease, Tokyo, Japan
| | - Shunpei Okada
- Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Masamichi Muramatsu
- Department of Infectious Disease Research, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Hisashi Iizasa
- Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
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Leong S, Nasser H, Ikeda T. APOBEC3-Related Editing and Non-Editing Determinants of HIV-1 and HTLV-1 Restriction. Int J Mol Sci 2025; 26:1561. [PMID: 40004025 PMCID: PMC11855278 DOI: 10.3390/ijms26041561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/09/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3/A3) family of cytosine deaminases serves as a key innate immune barrier against invading retroviruses and endogenous retroelements. The A3 family's restriction activity against these parasites primarily arises from their ability to catalyze cytosine-to-uracil conversions, resulting in genome editing and the accumulation of lethal mutations in viral genomes. Additionally, non-editing mechanisms, including deaminase-independent pathways, such as blocking viral reverse transcription, have been proposed as antiviral strategies employed by A3 family proteins. Although viral factors can influence infection progression, the determinants that govern A3-mediated restriction are critical in shaping retroviral infection outcomes. This review examines the interactions between retroviruses, specifically human immunodeficiency virus type 1 and human T-cell leukemia virus type 1, and A3 proteins to better understand how editing and non-editing activities contribute to the trajectory of these retroviral infections.
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Affiliation(s)
- Sharee Leong
- Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
- Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hesham Nasser
- Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
| | - Terumasa Ikeda
- Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
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Simmonds P. C→U transition biases in SARS-CoV-2: still rampant 4 years from the start of the COVID-19 pandemic. mBio 2024; 15:e0249324. [PMID: 39475243 PMCID: PMC11633203 DOI: 10.1128/mbio.02493-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/24/2024] [Indexed: 12/12/2024] Open
Abstract
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pandemic and post-pandemic periods has been characterized by rapid adaptive changes that confer immune escape and enhanced human-to-human transmissibility. Sequence change is additionally marked by an excess number of C→U transitions suggested as being due to host-mediated genome editing. To investigate how these influence the evolutionary trajectory of SARS-CoV-2, 2,000 high-quality, coding complete genome sequences of SARS-CoV-2 variants collected pre-September 2020 and from each subsequently appearing alpha, delta, BA.1, BA.2, BA.5, XBB, EG, HK, and JN.1 lineages were downloaded from NCBI Virus in April 2024. C→U transitions were the most common substitution during the diversification of SARS-CoV-2 lineages over the 4-year observation period. A net loss of C bases and accumulation of U's occurred at a constant rate of approximately 0.2%-0.25%/decade. C→U transitions occurred in over a quarter of all sites with a C (26.5%; range 20.0%-37.2%) around five times more than observed for the other transitions (5.3%-6.8%). In contrast to an approximately random distribution of other transitions across the genome, most C→U substitutions occurred at statistically preferred sites in each lineage. However, only the most C→U polymorphic sites showed evidence for a preferred 5'U context previously associated with APOBEC 3A editing. There was a similarly weak preference for unpaired bases suggesting much less stringent targeting of RNA than mediated by A3 deaminases in DNA editing. Future functional studies are required to determine editing preferences, impacts on replication fitness in vivo of SARS-CoV-2 and other RNA viruses, and impact on host tropism. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pandemic and post-pandemic periods has shown a remarkable capacity to adapt and evade human immune responses and increase its human-to-human transmissibility. The genome of SARS-CoV-2 is also increasingly scarred by the effects of multiple C→U mutations from host genome editing as a cellular defense mechanism akin to restriction factors for retroviruses. Through the analysis of large data sets of SARS-CoV-2 isolate sequences collected throughout the pandemic period and beyond, we show that C→U transitions have driven a base compositional change over time amounting to a net loss of C bases and accumulation of U's at a rate of approximately 0.2%-0.25%/decade. Most C→U substitutions occurred in the absence of the preferred upstream-base context or targeting of unpaired RNA bases previously associated with the host RNA editing protein, APOBEC 3A. The analyses provide a series of testable hypotheses that can be experimentally investigated in the future.
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Affiliation(s)
- Peter Simmonds
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
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Lei Z, Wang L, Gao H, Guo S, Kang X, Yuan J, Lv Z, Jiang Y, Yi J, Chen Z, Wang G. Mechanisms underlying the compromised clinical efficacy of interferon in clearing HBV. Virol J 2024; 21:314. [PMID: 39633459 PMCID: PMC11619119 DOI: 10.1186/s12985-024-02589-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV's interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α's antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV's ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.
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Affiliation(s)
- Zhuoyan Lei
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Luye Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Hanlin Gao
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Shubian Guo
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Xinjian Kang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jiajun Yuan
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Ziying Lv
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Yuxin Jiang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jinping Yi
- Department of Clinical Laboratory, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Gang Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China.
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Sinha P, Thio CL, Balagopal A. Intracellular Host Restriction of Hepatitis B Virus Replication. Viruses 2024; 16:764. [PMID: 38793645 PMCID: PMC11125714 DOI: 10.3390/v16050764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
The hepatitis B virus (HBV) infects hepatocytes and hijacks host cellular mechanisms for its replication. Host proteins can be frontline effectors of the cell's defense and restrict viral replication by impeding multiple steps during its intracellular lifecycle. This review summarizes many of the well-described restriction factors, their mechanisms of restriction, and counteractive measures of HBV, with a special focus on viral transcription. We discuss some of the limitations and knowledge gaps about the restriction factors, highlighting how these factors may be harnessed to facilitate therapeutic strategies against HBV.
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Affiliation(s)
| | | | - Ashwin Balagopal
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (P.S.); (C.L.T.)
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Lovšin N, Gangupam B, Bergant Marušič M. The Intricate Interplay between APOBEC3 Proteins and DNA Tumour Viruses. Pathogens 2024; 13:187. [PMID: 38535531 PMCID: PMC10974850 DOI: 10.3390/pathogens13030187] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/17/2024] [Indexed: 02/11/2025] Open
Abstract
APOBEC3 proteins are cytidine deaminases that play a crucial role in the innate immune response against viruses, including DNA viruses. Their main mechanism for restricting viral replication is the deamination of cytosine to uracil in viral DNA during replication. This process leads to hypermutation of the viral genome, resulting in loss of viral fitness and, in many cases, inactivation of the virus. APOBEC3 proteins inhibit the replication of a number of DNA tumour viruses, including herpesviruses, papillomaviruses and hepadnaviruses. Different APOBEC3s restrict the replication of different virus families in different ways and this restriction is not limited to one APOBEC3. Infection with DNA viruses often leads to the development and progression of cancer. APOBEC3 mutational signatures have been detected in various cancers, indicating the importance of APOBEC3s in carcinogenesis. Inhibition of DNA viruses by APOBEC3 proteins appears to play a dual role in this process. On the one hand, it is an essential component of the innate immune response to viral infections, and, on the other hand, it contributes to the pathogenesis of persistent viral infections and the progression of cancer. The current review examines the complex interplay between APOBEC3 proteins and DNA viruses and sheds light on the mechanisms of action, viral countermeasures and the impact on carcinogenesis. Deciphering the current issues in the interaction of APOBEC/DNA viruses should enable the development of new targeted cancer therapies.
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Affiliation(s)
- Nika Lovšin
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia;
| | - Bhavani Gangupam
- Laboratory for Environmental and Life Sciences, University of Nova Gorica, Vipavska 13, 5000 Nova Gorica, Slovenia;
| | - Martina Bergant Marušič
- Laboratory for Environmental and Life Sciences, University of Nova Gorica, Vipavska 13, 5000 Nova Gorica, Slovenia;
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Zhao Q, Liu H, Tang L, Wang F, Tolufashe G, Chang J, Guo JT. Mechanism of interferon alpha therapy for chronic hepatitis B and potential approaches to improve its therapeutic efficacy. Antiviral Res 2024; 221:105782. [PMID: 38110058 DOI: 10.1016/j.antiviral.2023.105782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Hepatitis B virus (HBV) chronically infects 296 million people worldwide and causes more than 820,000 deaths annually due to cirrhosis and hepatocellular carcinoma. Current standard-of-care medications for chronic hepatitis B (CHB) include nucleos(t)ide analogue (NA) viral DNA polymerase inhibitors and pegylated interferon alpha (PEG-IFN-α). NAs can efficiently suppress viral replication and improve liver pathology, but not eliminate or inactivate HBV covalently closed circular DNA (cccDNA). CCC DNA is the most stable HBV replication intermediate that exists as a minichromosome in the nucleus of infected hepatocyte to transcribe viral RNA and support viral protein translation and genome replication. Consequentially, a finite duration of NA therapy rarely achieves a sustained off-treatment suppression of viral replication and life-long NA treatment is most likely required. On the contrary, PEG-IFN-α has the benefit of finite treatment duration and achieves HBsAg seroclearance, the indication of durable immune control of HBV replication and functional cure of CHB, in approximately 5% of treated patients. However, the low antiviral efficacy and poor tolerability limit its use. Understanding how IFN-α suppresses HBV replication and regulates antiviral immune responses will help rational optimization of IFN therapy and development of novel immune modulators to improve the rate of functional cure. This review article highlights mechanistic insight on IFN control of HBV infection and recent progress in development of novel IFN regimens, small molecule IFN mimetics and combination therapy of PEG-IFN-α with new direct-acting antivirals and therapeutic vaccines to facilitate the functional cure of CHB.
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Affiliation(s)
- Qiong Zhao
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Hui Liu
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Liudi Tang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Fuxuan Wang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | | | - Jinhong Chang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, United States.
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Zhang K, Chen F, Shen HY, Zhang PP, Gao H, Peng H, Luo YS, Cheng ZS. Regulatory variants of APOBEC3 genes potentially associate with COVID-19 severity in populations with African ancestry. Sci Rep 2023; 13:22435. [PMID: 38105291 PMCID: PMC10725877 DOI: 10.1038/s41598-023-49791-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023] Open
Abstract
Since November 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the worldwide pandemic of the coronavirus disease 2019 (COVID-19), the impact of which is huge to the lives of world populations. Many studies suggested that such situation will continue due to the endless mutations in SARS-CoV-2 genome that result in complexity of the efforts for the control of SARS-CoV-2, since the special enrichment of nucleotide substitution C>U in SARS-CoV-2 sequences were discovered mainly due to the editing by human host factors APOBEC3 genes. The observation of SARS-CoV-2 variants Beta (B.1.351) and Omicron (B.1.1.529) firstly spreading in South Africa promoted us to hypothesize that genetic variants of APOBEC3 special in African populations may be attributed to the higher mutation rate of SARS-CoV-2 variants in Africa. Current study was conducted to search for functional variants of APOBEC3 genes associate with COVID-19 hospitalization in African population. By integrating data from the 1000 Genomes Project, Genotype-Tissue Expression (GTEx), and Host Genetics Initiative (HGI) of COVID-19, we identified potential functional SNPs close to APOBEC3 genes that are associated with COVID-19 hospitalization in African but not with other populations. Our study provides new insights on the potential contribution of APOBEC3 genes on the evolution of SARS-CoV-2 mutations in African population, but further replication is needed to confirm our results.
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Affiliation(s)
- Ke Zhang
- The Key and Characteristic Laboratory of Modern Pathogenicity Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 561113, China
| | - Fang Chen
- The Key and Characteristic Laboratory of Modern Pathogenicity Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 561113, China
| | - Hu-Yan Shen
- The Key and Characteristic Laboratory of Modern Pathogenicity Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 561113, China
| | - Ping-Ping Zhang
- The Key and Characteristic Laboratory of Modern Pathogenicity Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 561113, China
| | - Han Gao
- The Department of Emergency ICU, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Hong Peng
- The Department of Emergency ICU, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Yu-Si Luo
- The Department of Emergency ICU, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
- The Department of Emergency, Liupanshui Hospital of The Affiliated Hospital of Guizhou Medical University, Liupanshui, 553000, China.
| | - Zhong-Shan Cheng
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Hospital, MS1122, Memphis, TN, 38105, USA.
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Suspène R, Raymond KA, Boutin L, Guillier S, Lemoine F, Ferraris O, Tournier JN, Iseni F, Simon-Lorière E, Vartanian JP. APOBEC3F Is a Mutational Driver of the Human Monkeypox Virus Identified in the 2022 Outbreak. J Infect Dis 2023; 228:1421-1429. [PMID: 37224627 PMCID: PMC11009509 DOI: 10.1093/infdis/jiad165] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/24/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND On May 6, 2022, a powerful outbreak of monkeypox virus (MPXV) had been reported outside of Africa, with many continuing new cases being reported around the world. Analysis of mutations among the 2 different lineages present in the 2021 and 2022 outbreaks revealed the presence of G->A mutations occurring in the 5'GpA context, indicative of APOBEC3 cytidine deaminase activity. METHODS By using a sensitive polymerase chain reaction (differential DNA denaturation PCR) method allowing differential amplification of AT-rich DNA, we analyzed the level of APOBEC3-induced MPXV editing in infected cells and in patients. RESULTS We demonstrate that G->A hypermutated MPXV genomes can be recovered experimentally from APOBEC3 transfection followed by MPXV infection. Here, among the 7 human APOBEC3 cytidine deaminases (A3A-A3C, A3DE, A3F-A3H), only APOBEC3F was capable of extensively deaminating cytidine residues in MPXV genomes. Hyperedited genomes were also recovered in ∼42% of analyzed patients. Moreover, we demonstrate that substantial repair of these mutations occurs. Upon selection, corrected G->A mutations escaping drift loss contribute to the MPXV evolution observed in the current epidemic. CONCLUSIONS Stochastic or transient overexpression of the APOBEC3F gene exposes the MPXV genome to a broad spectrum of mutations that may be modeling the mutational landscape after multiple cycles of viral replication.
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Affiliation(s)
- Rodolphe Suspène
- Virus and Cellular Stress Unit, Department of Virology, Institut Pasteur, Université de Paris Cité, Paris, France
| | - Kyle A Raymond
- Virus and Cellular Stress Unit, Department of Virology, Institut Pasteur, Université de Paris Cité, Paris, France
- Sorbonne Université, Complexité du Vivant, Paris, France
| | - Laetitia Boutin
- Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
- Institut de Recherche Biomédicale des Armées, National Reference Center for Orthopoxviruses, (CNR-LE Orthopoxvirus), Brétigny-sur-Orge, France
| | - Sophie Guillier
- Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
| | - Frédéric Lemoine
- Institut Pasteur, Université Paris Cité, G5 Evolutionary Genomics of RNA Viruses, Paris, France
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - Olivier Ferraris
- Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
- Institut de Recherche Biomédicale des Armées, National Reference Center for Orthopoxviruses, (CNR-LE Orthopoxvirus), Brétigny-sur-Orge, France
| | - Jean-Nicolas Tournier
- Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
- Ecole du Val-de-Grâce, Paris, France
| | - Frédéric Iseni
- Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
| | - Etienne Simon-Lorière
- Institut Pasteur, Université Paris Cité, G5 Evolutionary Genomics of RNA Viruses, Paris, France
| | - Jean-Pierre Vartanian
- Virus and Cellular Stress Unit, Department of Virology, Institut Pasteur, Université de Paris Cité, Paris, France
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De La Cruz-Montoya AH, Díaz Velásquez CE, Martínez-Gregorio H, Ruiz-De La Cruz M, Bustos-Arriaga J, Castro-Jiménez TK, Olguín-Hernández JE, Rodríguez-Sosa M, Terrazas-Valdes LI, Jiménez-Alvarez LA, Regino-Zamarripa NE, Ramírez-Martínez G, Cruz-Lagunas A, Peralta-Arrieta I, Armas-López L, Contreras-Garza BM, Palma-Cortés G, Cabello-Gutierrez C, Báez-Saldaña R, Zúñiga J, Ávila-Moreno F, Vaca-Paniagua F. Molecular transition of SARS-CoV-2 from critical patients during the first year of the COVID-19 pandemic in Mexico City. Front Cell Infect Microbiol 2023; 13:1155938. [PMID: 37260697 PMCID: PMC10227454 DOI: 10.3389/fcimb.2023.1155938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/02/2023] [Indexed: 06/02/2023] Open
Abstract
Background The SARS-CoV-2 virus has caused unprecedented mortality since its emergence in late 2019. The continuous evolution of the viral genome through the concerted action of mutational forces has produced distinct variants that became dominant, challenging human immunity and vaccine development. Aim and methods In this work, through an integrative genomic approach, we describe the molecular transition of SARS-CoV-2 by analyzing the viral whole genome sequences from 50 critical COVID-19 patients recruited during the first year of the pandemic in Mexico City. Results Our results revealed differential levels of the evolutionary forces across the genome and specific mutational processes that have shaped the first two epidemiological waves of the pandemic in Mexico. Through phylogenetic analyses, we observed a genomic transition in the circulating SARS-CoV-2 genomes from several lineages prevalent in the first wave to a dominance of the B.1.1.519 variant (defined by T478K, P681H, and T732A mutations in the spike protein) in the second wave. Conclusion This work contributes to a better understanding of the evolutionary dynamics and selective pressures that act at the genomic level, the prediction of more accurate variants of clinical significance, and a better comprehension of the molecular mechanisms driving the evolution of SARS-CoV-2 to improve vaccine and drug development.
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Affiliation(s)
- Aldo Hugo De La Cruz-Montoya
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Clara Estela Díaz Velásquez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Héctor Martínez-Gregorio
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Miguel Ruiz-De La Cruz
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Avenida Instituto Politécnico Nacional, Colonia San Pedro Zacatenco, Delegación Gustavo A. Madero, Ciudad de México, Mexico
| | - José Bustos-Arriaga
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Tannya Karen Castro-Jiménez
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Jonadab Efraín Olguín-Hernández
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
| | - Miriam Rodríguez-Sosa
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Luis Ignacio Terrazas-Valdes
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Luis Armando Jiménez-Alvarez
- Laboratorio de Inmunobiología y Genética y Departamento de Virología, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Nora Elemi Regino-Zamarripa
- Laboratorio de Inmunobiología y Genética y Departamento de Virología, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ciudad de México, Mexico
| | - Gustavo Ramírez-Martínez
- Laboratorio de Inmunobiología y Genética y Departamento de Virología, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Alfredo Cruz-Lagunas
- Laboratorio de Inmunobiología y Genética y Departamento de Virología, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Irlanda Peralta-Arrieta
- Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Leonel Armas-López
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | | | - Gabriel Palma-Cortés
- Department of Research in Virology and Mycology, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Carlos Cabello-Gutierrez
- Department of Research in Virology and Mycology, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Renata Báez-Saldaña
- Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Joaquín Zúñiga
- Laboratorio de Inmunobiología y Genética y Departamento de Virología, Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ciudad de México, Mexico
- Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
| | - Federico Ávila-Moreno
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
- Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas, Ciudad de México, Mexico
- Laboratorio 12 de Enfermedades Pulmonares y Epigenómica del Cáncer, Unidad de Investigación en Biomedicina (UBIMED), Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Felipe Vaca-Paniagua
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, Mexico
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, Mexico
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11
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Roelofs PA, Martens JW, Harris RS, Span PN. Clinical Implications of APOBEC3-Mediated Mutagenesis in Breast Cancer. Clin Cancer Res 2023; 29:1658-1669. [PMID: 36478188 PMCID: PMC10159886 DOI: 10.1158/1078-0432.ccr-22-2861] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/30/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022]
Abstract
Over recent years, members of the APOBEC3 family of cytosine deaminases have been implicated in increased cancer genome mutagenesis, thereby contributing to intratumor and intertumor genomic heterogeneity and therapy resistance in, among others, breast cancer. Understanding the available methods for clinical detection of these enzymes, the conditions required for their (dysregulated) expression, the clinical impact they have, and the clinical implications they may offer is crucial in understanding the current impact of APOBEC3-mediated mutagenesis in breast cancer. Here, we provide a comprehensive review of recent developments in the detection of APOBEC3-mediated mutagenesis and responsible APOBEC3 enzymes, summarize the pathways that control their expression, and explore the clinical ramifications and opportunities they pose. We propose that APOBEC3-mediated mutagenesis can function as a helpful predictive biomarker in several standard-of-care breast cancer treatment plans and may be a novel target for treatment.
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Affiliation(s)
- Pieter A. Roelofs
- Department of Radiation Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - John W.M. Martens
- Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
| | - Reuben S. Harris
- Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Paul N. Span
- Department of Radiation Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
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12
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Zhu T, Niu G, Zhang Y, Chen M, Li CY, Hao L, Zhang Z. Host-mediated RNA editing in viruses. Biol Direct 2023; 18:12. [PMID: 36978112 PMCID: PMC10043548 DOI: 10.1186/s13062-023-00366-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Viruses rely on hosts for life and reproduction, cause a variety of symptoms from common cold to AIDS to COVID-19 and provoke public health threats claiming millions of lives around the globe. RNA editing, as a crucial co-/post-transcriptional modification inducing nucleotide alterations on both endogenous and exogenous RNA sequences, exerts significant influences on virus replication, protein synthesis, infectivity and toxicity. Hitherto, a number of host-mediated RNA editing sites have been identified in diverse viruses, yet lacking a full picture of RNA editing-associated mechanisms and effects in different classes of viruses. Here we synthesize the current knowledge of host-mediated RNA editing in a variety of viruses by considering two enzyme families, viz., ADARs and APOBECs, thereby presenting a landscape of diverse editing mechanisms and effects between viruses and hosts. In the ongoing pandemic, our study promises to provide potentially valuable insights for better understanding host-mediated RNA editing on ever-reported and newly-emerging viruses.
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Affiliation(s)
- Tongtong Zhu
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Guangyi Niu
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuansheng Zhang
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ming Chen
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chuan-Yun Li
- Laboratory of Bioinformatics and Genomic Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
| | - Lili Hao
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- China National Center for Bioinformation, Beijing, 100101, China.
| | - Zhang Zhang
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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13
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Manjunath L, Oh S, Ortega P, Bouin A, Bournique E, Sanchez A, Martensen PM, Auerbach AA, Becker JT, Seldin M, Harris RS, Semler BL, Buisson R. APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection. Nat Commun 2023; 14:820. [PMID: 36781883 PMCID: PMC9925369 DOI: 10.1038/s41467-023-36445-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 01/31/2023] [Indexed: 02/15/2023] Open
Abstract
Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find that APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances the PKR-suppressing activity of ADAR1 in response to infection by many types of viruses. This leads to translational blockage and the formation of stress granules. Furthermore, we show that APOBEC3B localizes to stress granules through the interaction with PABPC1. APOBEC3B facilitates the formation of protein-RNA condensates with stress granule assembly factor (G3BP1) by protecting mRNA associated with stress granules from RNAse L-induced RNA cleavage during viral infection. These results not only reveal that APOBEC3B is a key regulator of different steps of the innate immune response throughout viral infection but also highlight an alternative mechanism by which APOBEC3B can impact virus replication without editing viral genomes.
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Affiliation(s)
- Lavanya Manjunath
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Sunwoo Oh
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Pedro Ortega
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Alexis Bouin
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Elodie Bournique
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Ambrocio Sanchez
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Pia Møller Martensen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
| | - Ashley A Auerbach
- Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA
- Institute for Molecular Virology, University of Minnesota - Twin Cities, Minneapolis, MN, USA
| | - Jordan T Becker
- Institute for Molecular Virology, University of Minnesota - Twin Cities, Minneapolis, MN, USA
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota - Twin Cities, Minneapolis, MN, USA
| | - Marcus Seldin
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Reuben S Harris
- Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA
- Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Bert L Semler
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Rémi Buisson
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
- Center for Virus Research, University of California Irvine, Irvine, CA, USA.
- Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA.
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14
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The APOBEC3B cytidine deaminase is an adenovirus restriction factor. PLoS Pathog 2023; 19:e1011156. [PMID: 36745676 PMCID: PMC9934312 DOI: 10.1371/journal.ppat.1011156] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 02/16/2023] [Accepted: 01/26/2023] [Indexed: 02/07/2023] Open
Abstract
Human adenoviruses (HAdVs) are a large family of DNA viruses counting more than a hundred strains divided into seven species (A to G). HAdVs induce respiratory tract infections, gastroenteritis and conjunctivitis. APOBEC3B is a cytidine deaminase that restricts several DNA viruses. APOBEC3B is also implicated in numerous cancers where it is responsible for the introduction of clustered mutations into the cellular genome. In this study, we demonstrate that APOBEC3B is an adenovirus restriction factor acting through a deaminase-dependent mechanism. APOBEC3B introduces C-to-T clustered mutations into the adenovirus genome. APOBEC3B reduces the propagation of adenoviruses by limiting viral genome replication, progression to late phase, and production of infectious virions. APOBEC3B restriction efficiency varies between adenoviral strains, the A12 strain being more sensitive to APOBEC3B than the B3 or C2 strains. In A12-infected cells, APOBEC3B clusters in the viral replication centers. Importantly, we show that adenovirus infection leads to a reduction of the quantity and/or enzymatic activity of the APOBEC3B protein depending on the strains. The A12 strain seems less able to resist APOBEC3B than the B3 or C2 strains, a characteristic which could explain the strong depletion of the APOBEC3-targeted motifs in the A12 genome. These findings suggest that adenoviruses evolved different mechanisms to antagonize APOBEC3B. Elucidating these mechanisms could benefit the design of cancer treatments. This study also identifies adenoviruses as triggers of the APOBEC3B-mediated innate response. The involvement of certain adenoviral strains in the genesis of the APOBEC3 mutational signature observed in tumors deserves further study.
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15
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Influence of viral genome properties on polymerase fidelity. Trends Genet 2023; 39:9-14. [PMID: 36402624 DOI: 10.1016/j.tig.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 10/27/2022] [Accepted: 10/30/2022] [Indexed: 11/17/2022]
Abstract
The first step of viral evolution takes place during genome replication via the error-prone viral polymerase. Among the mutants that arise through this process, only a few well-adapted variants will be selected by natural selection, renewing the viral genome population. Viral polymerase-mediated errors are thought to occur stochastically. However, accumulating evidence suggests that viral polymerase-mediated mutations are heterogeneously distributed throughout the viral genome. Here, we review work that supports this concept and provides mechanistic insights into how specific features of the viral genome could modulate viral polymerase-mediated errors. A predisposition to accumulate viral polymerase-mediated errors at specific loci in the viral genome may guide evolution to specific pathways, thus opening new directions of research to better understand viral evolutionary dynamics.
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16
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Moraes SN, Becker JT, Moghadasi SA, Shaban NM, Auerbach AA, Cheng AZ, Harris RS. Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases. eLife 2022; 11:83893. [PMID: 36458685 DOI: 10.7554/elife.83893] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 10/12/2022] [Indexed: 12/04/2022] Open
Abstract
Viruses have evolved diverse mechanisms to antagonize host immunity such as direct inhibition and relocalization of cellular APOBEC3B (A3B) by the ribonucleotide reductase (RNR) of Epstein-Barr virus. Here, we investigate the mechanistic conservation and evolutionary origin of this innate immune counteraction strategy. First, we find that human gamma-herpesvirus RNRs engage A3B via largely distinct surfaces. Second, we show that RNR-mediated enzymatic inhibition and relocalization of A3B depend upon binding to different regions of the catalytic domain. Third, we show that the capability of viral RNRs to antagonize A3B is conserved among gamma-herpesviruses that infect humans and Old World monkeys that encode this enzyme but absent in homologous viruses that infect New World monkeys that naturally lack the A3B gene. Finally, we reconstruct the ancestral primate A3B protein and demonstrate that it is active and similarly engaged by the RNRs from viruses that infect humans and Old World monkeys but not by the RNRs from viruses that infect New World monkeys. These results combine to indicate that the birth of A3B at a critical branchpoint in primate evolution may have been a driving force in selecting for an ancestral gamma-herpesvirus with an expanded RNR functionality through counteraction of this antiviral enzyme.
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Affiliation(s)
- Sofia N Moraes
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States
| | - Jordan T Becker
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States
| | - Seyed Arad Moghadasi
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States
| | - Nadine M Shaban
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States
| | - Ashley A Auerbach
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States.,Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, United States
| | - Adam Z Cheng
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States
| | - Reuben S Harris
- Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota, Minneapolis, United States.,Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, United States.,Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, United States
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17
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Hu J, Wang H, Yang L, Wu S, Li Y, Li Y, Li Z. Compound IMB-Z inhibits hepatitis B virus replication through increasing APOBEC3G expression and incorporation into viral nucleocapsids. J Glob Antimicrob Resist 2022; 31:371-378. [PMID: 36396043 DOI: 10.1016/j.jgar.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 09/01/2022] [Accepted: 11/04/2022] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES As a host restriction factor, apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) has been shown to suppress the replication of several viruses including hepatitis B virus (HBV). Recently, we reported that IMB-Z, a N-phenylbenzamide derivative, could inhibit Enterovirus 71 replication, and A3G mediated its antiviral activity. Whether IMB-Z exhibits an inhibitory effect on HBV replication has not been investigated. MATERIAL AND METHODS HBV DNA, pregenomic RNA (pgRNA), core protein, and capsid levels were determined by a qPCR assay or Southern blot, Northern blot, Western blot, and particle gel assay, respectively. Mutation analysis of HBV DNAs was conducted by a differential DNA denaturation PCR assay. A3G encapsidation into HBV nucleocapsids was examined by Western blot analysis after ultracentrifugation and a co-immunoprecipitation (IP) assay between HBV core and A3G proteins. RESULTS In the present study, we found that IMB-Z could considerably inhibit HBV replication in HepAD38 cells. Interestingly, IMB-Z did not alter the HBV pgRNA production but could reduce the level of core protein, viral nucleocapsids, and core-associated DNA, as well as cccDNA intracellular amplification. Similar to the action of IMB-Z's inhibition of Enterovirus 71 replication, we found that IMB-Z's inhibition of HBV replication was associated with increased level of A3G. Mechanistically, we demonstrated that the inhibitory effect of IMB-Z is independent of the cytidine deaminase activity of A3G and is exerted by increasing its incorporation into viral nucleocapsids. CONCLUSIONS Our results indicate that IMB-Z inhibits HBV through pharmacological induction A3G expression and incorporation into HBV nucleocapsids.
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Affiliation(s)
- Jin Hu
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huiqiang Wang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lu Yang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuo Wu
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yanping Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yuhuan Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Zhuorong Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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18
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Martinez MG, Smekalova E, Combe E, Gregoire F, Zoulim F, Testoni B. Gene Editing Technologies to Target HBV cccDNA. Viruses 2022; 14:v14122654. [PMID: 36560658 PMCID: PMC9787400 DOI: 10.3390/v14122654] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Hepatitis B virus (HBV) remains a significant cause of mortality and morbidity worldwide, since chronic HBV infection is associated with elevated risk of cirrhosis and hepatocellular carcinoma. Current licensed therapies against HBV efficiently suppress viral replication; however, they do not have significant effects on the intrahepatic covalently closed circular DNA (cccDNA) of the viral minichromosome responsible for viral persistence. Thus, life-long treatment is required to avoid viral rebound. There is a significant need for novel therapies that can reduce, silence or eradicate cccDNA, thus preventing HBV reemergence after treatment withdrawal. In this review, we discuss the latest developments and applications of gene editing and related approaches for directly targeting HBV DNA and, more specifically, cccDNA in infected hepatocytes.
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Affiliation(s)
| | | | - Emmanuel Combe
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
| | | | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
- Hospices Civils de Lyon (HCL), 69002 Lyon, France
- Université Claude-Bernard Lyon 1 (UCBL1), 69008 Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
- Université Claude-Bernard Lyon 1 (UCBL1), 69008 Lyon, France
- Correspondence:
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19
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Abstract
Human papillomavirus (HPV) infection is a causative agent of multiple human cancers, including cervical and head and neck cancers. In these HPV-positive tumors, somatic mutations are caused by aberrant activation of DNA mutators such as members of the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of cytidine deaminases. APOBEC3 proteins are most notable for their restriction of various viruses, including anti-HPV activity. However, the potential role of APOBEC3 proteins in HPV-induced cancer progression has recently garnered significant attention. Ongoing research stems from the observations that elevated APOBEC3 expression is driven by HPV oncogene expression and that APOBEC3 activity is likely a significant contributor to somatic mutagenesis in HPV-positive cancers. This review focuses on recent advances in the study of APOBEC3 proteins and their roles in HPV infection and HPV-driven oncogenesis. Further, we discuss critical gaps and unanswered questions in our understanding of APOBEC3 in virus-associated cancers.
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Affiliation(s)
- Cody J Warren
- BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA
| | - Mario L Santiago
- Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA;
| | - Dohun Pyeon
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA;
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20
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Zhang X, Wu Z, Hao Y, Yu T, Li X, Liang Y, Li J, Huang L, Xu Y, Li X, Xu X, Wang W, Xu G, Zhang X, Lv Q, Fang Y, Xu R, Qian W. Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma. Front Immunol 2022; 13:888250. [PMID: 35592333 PMCID: PMC9112561 DOI: 10.3389/fimmu.2022.888250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.
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Affiliation(s)
- Xuzhao Zhang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou, China
| | - Zhaoxing Wu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yuanyuan Hao
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Teng Yu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xian Li
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yun Liang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jinfan Li
- Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Liansheng Huang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yang Xu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiuzhen Li
- Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaohua Xu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Weiqin Wang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Genbo Xu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohong Zhang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qinghua Lv
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yongming Fang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Rongzhen Xu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Wenbin Qian
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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21
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Kitamura K, Fukano K, Que L, Li Y, Wakae K, Muramatsu M. Activities of endogenous APOBEC3s and uracil-DNA-glycosylase affect the hypermutation frequency of hepatitis B virus cccDNA. J Gen Virol 2022; 103. [PMID: 35438620 DOI: 10.1099/jgv.0.001732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) plays a key role in the persistence of viral infection. We have previously shown that overexpression of an antiviral factor APOBEC3G (A3G) induces hypermutation in duck HBV (DHBV) cccDNA, whereas uracil-DNA-glycosylase (UNG) reduces these mutations. In this study, using cell-culture systems, we examined whether endogenous A3s and UNG affect HBV cccDNA mutation frequency. IFNγ stimulation induced a significant increase in endogenous A3G expression and cccDNA hypermutation. UNG inhibition enhanced the IFNγ-mediated hypermutation frequency. Transfection of reconstructed cccDNA revealed that this enhanced hypermutation caused a reduction in viral replication. These results suggest that the balance of endogenous A3s and UNG activities affects HBV cccDNA mutation and replication competency.
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Affiliation(s)
- Kouichi Kitamura
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Kento Fukano
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Lusheng Que
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Yingfang Li
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Kousho Wakae
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
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22
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Shilova ON, Tsyba DL, Shilov ES. Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis. Mol Biol 2022; 56:46-58. [PMID: 35194245 PMCID: PMC8852905 DOI: 10.1134/s002689332201006x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/23/2021] [Accepted: 06/01/2021] [Indexed: 01/02/2023]
Abstract
Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intracellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.
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Affiliation(s)
- O. N. Shilova
- Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - D. L. Tsyba
- Pavlov First State Medical University, 197022 St. Petersburg, Russia
- Sirius University of Science and Technology, 354340 Sochi, Russia
| | - E. S. Shilov
- Faculty of Biology, Moscow State University, 119234 Moscow, Russia
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23
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Zhang Y, Chen X, Cao Y, Yang Z. Roles of APOBEC3 in hepatitis B virus (HBV) infection and hepatocarcinogenesis. Bioengineered 2021; 12:2074-2086. [PMID: 34043485 PMCID: PMC8806738 DOI: 10.1080/21655979.2021.1931640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 02/08/2023] Open
Abstract
APOBEC3 (A3) cytidine deaminases inhibit hepatitis B virus (HBV) infection and play vital roles in maintaining a variety of biochemical processes, including the regulation of protein expression and innate immunity. Emerging evidence indicates that the deaminated deoxycytidine biochemical activity of A3 proteins in single-stranded DNA makes them a double-edged sword. These enzymes can cause cellular genetic mutations at replication forks or within transcription bubbles, depending on the physiological state of the cell and the phase of the cell cycle. Under pathological conditions, aberrant expression of A3 genes with improper deaminase activity regulation may threaten genomic stability and eventually lead to cancer development. This review attempted to summarize the antiviral activities and underlying mechanisms of A3 editing enzymes in HBV infections. Moreover, the correlations between A3 genes and hepatocarcinogenesis were also elucidated.
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Affiliation(s)
- Yuan Zhang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiaorong Chen
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yajuan Cao
- Central Laboratory, Shanghai Pulmonary HospitalSchool of Medicine, Tongji University School of Medicine, Shanghai, China
- Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zongguo Yang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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24
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Asaoka M, Patnaik SK, Ishikawa T, Takabe K. Different members of the APOBEC3 family of DNA mutators have opposing associations with the landscape of breast cancer. Am J Cancer Res 2021; 11:5111-5125. [PMID: 34765315 PMCID: PMC8569370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/14/2021] [Indexed: 06/13/2023] Open
Abstract
APOBEC enzymes are strong mutagenic factors. In breast cancer, expression of APOBEC3B is increased and associated with mutation load and poor outcome. Other APOBEC3s can also mutate DNA but their clinical significance in breast cancer and its underpinnings have not been comprehensively studied. In our examination of 1,091 breast carcinoma cases, high expression of APOBEC3A or APOBEC3B genes was associated with greater tumor burden of mutations and other genomic aberrations. Expression of none of the five APOBEC3C-H genes had any correlation with these features, including T[C-T/G]W mutations, but their high expression levels indicated a robust anti-cancer immune response within tumors, with elevated CD8+ T cell abundance, T cell receptor diversity, and immune cytolytic activity. Concordantly, survival analyses of this and two other cohorts with > 3,000 patients each showed favorable prognostic benefit of high APOBEC3C-H expression for both cancer progression and mortality. A detrimental prognostic value was observed for APOBEC3A and APOBEC3B. Single-cell data revealed cancer epithelial and stromal immune cells as major sources of APOBEC3B and APOBEC3C-H expression in tumors, respectively. These observations on opposing associations with breast cancer of different APOBEC3s highlight the contrasting roles of these enzymes, promoting cancer through mutagenesis while antagonizing it through immune response.
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Affiliation(s)
- Mariko Asaoka
- Department of Breast Surgery, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Santosh K Patnaik
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York, USA
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Kazuaki Takabe
- Department of Breast Surgery, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York, USA
- Niigata University Graduate School of Medical and Dental SciencesNiigata, Japan
- Department of Surgery, Yokohama City UniversityYokohama, Japan
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25
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Martinez MG, Boyd A, Combe E, Testoni B, Zoulim F. Covalently closed circular DNA: The ultimate therapeutic target for curing HBV infections. J Hepatol 2021; 75:706-717. [PMID: 34051332 DOI: 10.1016/j.jhep.2021.05.013] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 12/16/2022]
Abstract
Current antiviral therapies, such as pegylated interferon-α and nucleos(t)ide analogues, effectively improve the quality of life of patients with chronic hepatitis B. However, they can only control the infection rather than curing infected hepatocytes. Complete HBV cure is hampered by the lack of therapies that can directly affect the viral minichromosome (in the form of covalently closed circular DNA [cccDNA]). Approaches currently under investigation in early clinical trials are aimed at achieving a functional cure, defined as the loss of HBsAg and undetectable HBV DNA levels in serum. However, achieving a complete HBV cure requires therapies that can directly target the cccDNA pool, either via degradation, lethal mutations or functional silencing. In this review, we discuss cutting-edge technologies that could lead to non-cytolytic direct cccDNA targeting and cure of infected hepatocytes.
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Affiliation(s)
| | - Anders Boyd
- Stichting HIV Monitoring, Amsterdam, the Netherlands; Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, the Netherlands
| | - Emmanuel Combe
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France
| | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France; University of Lyon, Université Claude- Bernard (UCBL), 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France.
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26
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Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways. Nat Commun 2021; 12:4917. [PMID: 34389714 PMCID: PMC8363607 DOI: 10.1038/s41467-021-25203-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 07/27/2021] [Indexed: 02/07/2023] Open
Abstract
APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.
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27
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Chen Z, Eggerman TL, Bocharov AV, Baranova IN, Vishnyakova TG, Patterson AP. APOBEC3-induced mutation of the hepatitis virus B DNA genome occurs during its viral RNA reverse transcription into (-)-DNA. J Biol Chem 2021; 297:100889. [PMID: 34181944 PMCID: PMC8321922 DOI: 10.1016/j.jbc.2021.100889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 11/17/2022] Open
Abstract
APOBEC3s are innate single-stranded DNA cytidine-to-uridine deaminases that catalyze mutations in both pathogen and human genomes with significant roles in human disease. However, how APOBEC3s mutate a single-stranded DNA that is available momentarily during DNA transcription or replication in vivo remains relatively unknown. In this study, utilizing hepatitis B virus (HBV) viral mutations, we evaluated the mutational characteristics of individual APOBEC3s with reference to the HBV replication process through HBV whole single-strand (-)-DNA genome mutation analyses. We found that APOBEC3s induced C-to-T mutations from the HBV reverse transcription start site continuing through the whole (-)-DNA transcript to the termination site with variable efficiency, in an order of A3B >> A3G > A3H-II or A3C. A3B had a 3-fold higher mutation efficiency than A3H-II or A3C with up to 65% of all HBV genomic cytidines being converted into uridines in a single mutation event, consistent with the A3B localized hypermutation signature in cancer, namely, kataegis. On the other hand, A3C expression led to a 3-fold higher number of mutation-positive HBV genome clones, although each individual clone had a lower number of C-to-T mutations. Like A3B, A3C preferred both 5'-TC and 5'-CC sequences, but to a lesser degree. The APOBEC3-induced HBV mutations were predominantly detected in the HBV rcDNA but were not detectable in other intermediates including HBV cccDNA and pgRNA by primer extension of their PCR amplification products. These data demonstrate that APOBEC3-induced HBV genome mutations occur predominantly when the HBV RNA genome was reversely transcribed into (-)-DNA in the viral capsid.
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Affiliation(s)
- Zhigang Chen
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Thomas L Eggerman
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Alexander V Bocharov
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Irina N Baranova
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Tatyana G Vishnyakova
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Amy P Patterson
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
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28
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Sadeghpour S, Khodaee S, Rahnama M, Rahimi H, Ebrahimi D. Human APOBEC3 Variations and Viral Infection. Viruses 2021; 13:1366. [PMID: 34372572 PMCID: PMC8310219 DOI: 10.3390/v13071366] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/13/2022] Open
Abstract
Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases.
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Affiliation(s)
- Shiva Sadeghpour
- Department of Biological Science, University of California Irvine, Irvine, CA 92697, USA;
| | - Saeideh Khodaee
- Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614335, Iran;
| | - Mostafa Rahnama
- Department of Plant Pathology, University of Kentucky, Lexington, KY 40546, USA;
| | - Hamzeh Rahimi
- Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran;
| | - Diako Ebrahimi
- Texas Biomedical Research Institute, San Antonio, TX 78227, USA
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29
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Yin J, Chen X, Li N, Han X, Liu W, Pu R, Wu T, Ding Y, Zhang H, Zhao J, Han X, Wang H, Cheng S, Cao G. Compartmentalized evolution of hepatitis B virus contributes differently to the prognosis of hepatocellular carcinoma. Carcinogenesis 2021; 42:461-470. [PMID: 33247709 DOI: 10.1093/carcin/bgaa127] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/26/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011-15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC.
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Affiliation(s)
- Jianhua Yin
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Xi Chen
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Nan Li
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Xuewen Han
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Wenbin Liu
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Rui Pu
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Ting Wu
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Yibo Ding
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Hongwei Zhang
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Jun Zhao
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China
| | - Xue Han
- Division of Chronic Diseases, Center for Disease Control and Prevention of Yangpu District, Shanghai, China
| | - Hongyang Wang
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
| | - Shuqun Cheng
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, 8 Panshan Rd, Yangpu District, Shanghai 200433, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
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30
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Simmonds P, Ansari MA. Extensive C->U transition biases in the genomes of a wide range of mammalian RNA viruses; potential associations with transcriptional mutations, damage- or host-mediated editing of viral RNA. PLoS Pathog 2021; 17:e1009596. [PMID: 34061905 PMCID: PMC8195396 DOI: 10.1371/journal.ppat.1009596] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/11/2021] [Accepted: 04/29/2021] [Indexed: 11/18/2022] Open
Abstract
The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution.
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Affiliation(s)
- Peter Simmonds
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - M. Azim Ansari
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
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Asadi-Asadabad S, Sarvnaz H, Amiri MM, Mobini M, Khoshnoodi J, Hojjat-Farsangi M, Jeddi-Tehrani M, Golsaz-Shirazi F, Shokri F. Influence of Pattern Recognition Receptor Ligands on Induction of Innate Immunity and Control of Hepatitis B Virus Infection. Viral Immunol 2021; 34:531-541. [PMID: 34030480 DOI: 10.1089/vim.2021.0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Failure of current therapies to cure chronic hepatitis B has led to renewed interest in therapies that stimulate the host immune system. APOBEC3 (A3) family enzymes have been shown to induce mutations in hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) leading to inhibition of HBV transcription and replication. Pattern recognition receptor (PRR) agonists have been reported to suppress HBV, but it is unclear whether these agonists induce A3 gene expression in hepatocytes. We, therefore, evaluated whether PRR signaling activates the expression of A3 genes and other innate immunity genes and restricts HBV infection. HepG2-sodium taurocholate cotransporting polypeptide (NTCP) cells were infected with HBV and treated with various PRR agonists. The level of HBV infection was subsequently assessed by measurement of HBV biomarkers, including HBV DNA, cccDNA, HBs, and HBe antigens in infected hepatocytes. Among all tested PRR ligands, only Poly(I:C)-HMW/LyoVec and Poly(I:C)-HMW significantly inhibited hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), HBV DNA, and cccDNA, whereas R848 and lipopolysaccharide (LPS) only showed significant inhibition on HBsAg and HBeAg, but not virus DNA. CpG and Pam3CSK4, on the other hand, had no significant inhibitory effect on any of the HBV infection parameters. Moreover, Poly(I:C)-HMW/LyoVec and Poly(I:C)-HMW were the only ligands that significantly increased IL-8 secretion. Interestingly, HBV infection reduced IL-8 secretion induced by Poly(I:C)-HMW and to a lesser extent Poly(I:C)-HMW/LyoVec. Poly(I:C)-HMW/LyoVec had a significant effect on increasing the expression level of A3F, A3G, A3H, TLR3, RIG-1, and MDA5 genes. Our data suggest that PRR agonists may control HBV infection through different mechanisms. The RIG-1 and MDA5 agonist, Poly(I:C)-HMW/LyoVec, seems to downregulate HBV infection through induction of A3 genes.
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Affiliation(s)
- Sahar Asadi-Asadabad
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamzeh Sarvnaz
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Amiri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mobini
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Jalal Khoshnoodi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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Golsaz-Shirazi F, Shokri F. Cross talk between hepatitis B virus and innate immunity of hepatocytes. Rev Med Virol 2021; 32:e2256. [PMID: 34021666 DOI: 10.1002/rmv.2256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022]
Abstract
Innate immunity plays a major role in controlling viral infections. Recent exploration of sodium taurocholate co-transporting polypeptide receptor as specific hepatitis B virus (HBV) receptor in human hepatocytes has provided appropriate cell culture tools to study the innate immunity of hepatocytes and its cross talk with HBV. In this review, we give a brief update on interaction between HBV and innate immunity using the currently available in vitro cellular models that support the complete life cycle of HBV. We will discuss how HBV can act as a 'stealth' virus to counteract the innate immune responses mediated by the pathogen recognition receptors of hepatocytes and escape the first line of surveillance of the host immune system. We give an overview of the cellular components of innate immunity that present in these in vitro models and discuss how activating these innate immunity components may contribute to the eradication of HBV infection.
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Affiliation(s)
- Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Wang G, Guan J, Khan NU, Li G, Shao J, Zhou Q, Xu L, Huang C, Deng J, Zhu H, Chen Z. Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus. Gut Pathog 2021; 13:22. [PMID: 33845868 PMCID: PMC8040234 DOI: 10.1186/s13099-021-00421-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.
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Affiliation(s)
- Gang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Nazif U Khan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Guojun Li
- Institute for Hepatology, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Disease, Shenzhen, 518112, Guangdong, China.,The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, China
| | - Junwei Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qihui Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Lichen Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jingwen Deng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions. Viruses 2021; 13:v13030497. [PMID: 33802945 PMCID: PMC8002816 DOI: 10.3390/v13030497] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/15/2021] [Accepted: 03/15/2021] [Indexed: 12/16/2022] Open
Abstract
Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of deaminase proteins that can catalyze the deamination of cytosine to uracil on single-stranded DNA or/and RNA. APOBEC proteins are involved in diverse biological functions, including adaptive and innate immunity, which are critical for restricting viral infection and endogenous retroelements. Dysregulation of their functions can cause undesired genomic mutations and RNA modification, leading to various associated diseases, such as hyper-IgM syndrome and cancer. This review focuses on the structural and biochemical data on the multimerization status of individual APOBECs and the associated functional implications. Many APOBECs form various multimeric complexes, and multimerization is an important way to regulate functions for some of these proteins at several levels, such as deaminase activity, protein stability, subcellular localization, protein storage and activation, virion packaging, and antiviral activity. The multimerization of some APOBECs is more complicated than others, due to the associated complex RNA binding modes.
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Riva G, Albano C, Gugliesi F, Pasquero S, Pacheco SFC, Pecorari G, Landolfo S, Biolatti M, Dell’Oste V. HPV Meets APOBEC: New Players in Head and Neck Cancer. Int J Mol Sci 2021; 22:1402. [PMID: 33573337 PMCID: PMC7866819 DOI: 10.3390/ijms22031402] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/28/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022] Open
Abstract
Besides smoking and alcohol, human papillomavirus (HPV) is a factor promoting head and neck squamous cell carcinoma (HNSCC). In some human tumors, including HNSCC, a number of mutations are caused by aberrantly activated DNA-modifying enzymes, such as the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) family of cytidine deaminases. As the enzymatic activity of APOBEC proteins contributes to the innate immune response to viruses, including HPV, the role of APOBEC proteins in HPV-driven head and neck carcinogenesis has recently gained increasing attention. Ongoing research efforts take the cue from two key observations: (1) APOBEC expression depends on HPV infection status in HNSCC; and (2) APOBEC activity plays a major role in HPV-positive HNSCC mutagenesis. This review focuses on recent advances on the role of APOBEC proteins in HPV-positive vs. HPV-negative HNSCC.
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Affiliation(s)
- Giuseppe Riva
- Otorhinolaryngology Division, Department of Surgical Sciences, University of Turin, 10126 Turin, Italy; (G.R.); (G.P.)
| | - Camilla Albano
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
| | - Francesca Gugliesi
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
| | - Selina Pasquero
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
| | - Sergio Fernando Castillo Pacheco
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
| | - Giancarlo Pecorari
- Otorhinolaryngology Division, Department of Surgical Sciences, University of Turin, 10126 Turin, Italy; (G.R.); (G.P.)
| | - Santo Landolfo
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
| | - Matteo Biolatti
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
| | - Valentina Dell’Oste
- Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy; (C.A.); (F.G.); (S.P.); (S.F.C.P.); (S.L.)
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36
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Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution. Virology 2021; 556:62-72. [PMID: 33545556 PMCID: PMC7831814 DOI: 10.1016/j.virol.2020.12.018] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/21/2020] [Accepted: 12/21/2020] [Indexed: 12/19/2022]
Abstract
Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. Consistent with the latter, APOBEC-like directional C→U transitions of genomic plus-strand RNA are greatly overrepresented in SARS-CoV-2 genome sequences of variants emerging during the COVID-19 pandemic. A C→U mutational process may leave evolutionary imprints on coronavirus genomes, including extensive homoplasy from editing and reversion at targeted sites and the occurrence of driven amino acid sequence changes in viral proteins. If sustained over longer periods, this process may account for the previously reported marked global depletion of C and excess of U bases in human seasonal coronavirus genomes. This review synthesizes the current knowledge on APOBEC evolution and function and the evidence of their role in APOBEC-mediated genome editing of SARS-CoV-2 and other coronaviruses.
SARS-CoV-2 sequence variants contain an overabundance of C- > U transitions C- > U transitions are the hallmark of the activity of APOBEC cytosine deaminases Further work is needed to determine APOBEC's role in coronavirus evolution
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Hakata Y, Miyazawa M. Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins. Microorganisms 2020; 8:microorganisms8121976. [PMID: 33322756 PMCID: PMC7764128 DOI: 10.3390/microorganisms8121976] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023] Open
Abstract
Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins (APOBEC3s) are deaminases that convert cytosines to uracils predominantly on a single-stranded DNA, and function as intrinsic restriction factors in the innate immune system to suppress replication of viruses (including retroviruses) and movement of retrotransposons. Enzymatic activity is supposed to be essential for the APOBEC3 antiviral function. However, it is not the only way that APOBEC3s exert their biological function. Since the discovery of human APOBEC3G as a restriction factor for HIV-1, the deaminase-independent mode of action has been observed. At present, it is apparent that both the deaminase-dependent and -independent pathways are tightly involved not only in combating viruses but also in human tumorigenesis. Although the deaminase-dependent pathway has been extensively characterized so far, understanding of the deaminase-independent pathway remains immature. Here, we review existing knowledge regarding the deaminase-independent antiretroviral functions of APOBEC3s and their molecular mechanisms. We also discuss the possible unidentified molecular mechanism for the deaminase-independent antiretroviral function mediated by mouse APOBEC3.
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Affiliation(s)
- Yoshiyuki Hakata
- Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan;
- Correspondence: ; Tel.: +81-72-367-7660
| | - Masaaki Miyazawa
- Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan;
- Kindai University Anti-Aging Center, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
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38
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The Role of APOBECs in Viral Replication. Microorganisms 2020; 8:microorganisms8121899. [PMID: 33266042 PMCID: PMC7760323 DOI: 10.3390/microorganisms8121899] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 12/14/2022] Open
Abstract
Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including HIV-1 Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to APOBEC selection for viral variants that enhance replication or avoid immune elimination.
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Jaguva Vasudevan AA, Balakrishnan K, Gertzen CGW, Borvető F, Zhang Z, Sangwiman A, Held U, Küstermann C, Banerjee S, Schumann GG, Häussinger D, Bravo IG, Gohlke H, Münk C. Loop 1 of APOBEC3C Regulates its Antiviral Activity against HIV-1. J Mol Biol 2020; 432:6200-6227. [PMID: 33068636 DOI: 10.1016/j.jmb.2020.10.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 10/09/2020] [Accepted: 10/09/2020] [Indexed: 01/10/2023]
Abstract
APOBEC3 deaminases (A3s) provide mammals with an anti-retroviral barrier by catalyzing dC-to-dU deamination on viral ssDNA. Within primates, A3s have undergone a complex evolution via gene duplications, fusions, arms race, and selection. Human APOBEC3C (hA3C) efficiently restricts the replication of viral infectivity factor (vif)-deficient Simian immunodeficiency virus (SIVΔvif), but for unknown reasons, it inhibits HIV-1Δvif only weakly. In catarrhines (Old World monkeys and apes), the A3C loop 1 displays the conserved amino acid pair WE, while the corresponding consensus sequence in A3F and A3D is the largely divergent pair RK, which is also the inferred ancestral sequence for the last common ancestor of A3C and of the C-terminal domains of A3D and A3F in primates. Here, we report that modifying the WE residues in hA3C loop 1 to RK leads to stronger interactions with substrate ssDNA, facilitating catalytic function, which results in a drastic increase in both deamination activity and in the ability to restrict HIV-1 and LINE-1 replication. Conversely, the modification hA3F_WE resulted only in a marginal decrease in HIV-1Δvif inhibition. We propose that the two series of ancestral gene duplications that generated A3C, A3D-CTD and A3F-CTD allowed neo/subfunctionalization: A3F-CTD maintained the ancestral RK residues in loop 1, while diversifying selection resulted in the RK → WE modification in Old World anthropoids' A3C, possibly allowing for novel substrate specificity and function.
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Affiliation(s)
- Ananda Ayyappan Jaguva Vasudevan
- Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Kannan Balakrishnan
- Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, India
| | - Christoph G W Gertzen
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre & Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, Jülich, Germany; Center for Structural Studies (CSS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Fanni Borvető
- Centre National de la Recherche Scientifique, Laboratory MIVEGEC (CNRS, IRD, Uni Montpellier), Montpellier, France
| | - Zeli Zhang
- Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Anucha Sangwiman
- Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrike Held
- Division of Medical Biotechnology, Paul-Ehrlich-Institute, Langen, Germany
| | | | - Sharmistha Banerjee
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, India
| | - Gerald G Schumann
- Division of Medical Biotechnology, Paul-Ehrlich-Institute, Langen, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ignacio G Bravo
- Centre National de la Recherche Scientifique, Laboratory MIVEGEC (CNRS, IRD, Uni Montpellier), Montpellier, France
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre & Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Carsten Münk
- Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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40
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The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol 2020; 17:618-634. [PMID: 32467580 DOI: 10.1038/s41575-020-0296-6] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
The global burden of hepatitis B virus (HBV) is enormous, with 257 million persons chronically infected, resulting in more than 880,000 deaths per year worldwide. HBV exists as nine different genotypes, which differ in disease progression, natural history and response to therapy. HBV is an ancient virus, with the latest reports greatly expanding the host range of the Hepadnaviridae (to include fish and reptiles) and casting new light on the origins and evolution of this viral family. Although there is an effective preventive vaccine, there is no cure for chronic hepatitis B, largely owing to the persistence of a viral minichromosome that is not targeted by current therapies. HBV persistence is also facilitated through aberrant host immune responses, possibly due to the diverse intra-host viral populations that can respond to host-mounted and therapeutic selection pressures. This Review summarizes current knowledge on the influence of HBV diversity on disease progression and treatment response and the potential effect on new HBV therapies in the pipeline. The mechanisms by which HBV diversity can occur both within the individual host and at a population level are also discussed.
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Hix MA, Wong L, Flath B, Chelico L, Cisneros GA. Single-nucleotide polymorphism of the DNA cytosine deaminase APOBEC3H haplotype I leads to enzyme destabilization and correlates with lung cancer. NAR Cancer 2020; 2:zcaa023. [PMID: 32984821 PMCID: PMC7503452 DOI: 10.1093/narcan/zcaa023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/24/2020] [Accepted: 08/28/2020] [Indexed: 12/12/2022] Open
Abstract
A number of APOBEC family DNA cytosine deaminases can induce mutations in tumor cells. APOBEC3H haplotype I is one of the deaminases that has been proposed to cause mutations in lung cancer. Here, we confirmed that APOBEC3H haplotype I can cause uracil-induced DNA damage in lung cancer cells that results in γH2AX foci. Interestingly, the database of cancer biomarkers in DNA repair genes (DNArCdb) identified a single-nucleotide polymorphism (rs139298) of APOBEC3H haplotype I that is involved in lung cancer. While we thought this may increase the activity of APOBEC3H haplotype I, instead we found through computational modeling and cell-based experiments that this single-nucleotide polymorphism causes the destabilization of APOBEC3H Haplotype I. Computational analysis suggests that the resulting K121E change affects the structure of APOBEC3H leading to active site disruption and destabilization of the RNA-mediated dimer interface. A K117E mutation in a K121E background stabilized the APOBEC3H haplotype I, thus enabling biochemical study. Subsequent analysis showed that K121E affected catalytic activity, single-stranded DNA binding and oligomerization on single-stranded DNA. The destabilization of a DNA mutator associated with lung cancer supports the model that too much APOBEC3-induced mutation could result in immune recognition or death of tumor cells.
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Affiliation(s)
- Mark A Hix
- Department of Chemistry, University of North Texas, Denton, TX 76201, USA
| | - Lai Wong
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Ben Flath
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Linda Chelico
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - G Andrés Cisneros
- Department of Chemistry, University of North Texas, Denton, TX 76201, USA
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42
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Cui AL, Sun WF, Zhong ZJ, Jin J, Xue ST, Wu S, Li YH, Li ZR. Synthesis and Bioactivity of N-(4-Chlorophenyl)-4-Methoxy-3-(Methylamino) Benzamide as a Potential Anti-HBV Agent. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:3723-3729. [PMID: 32982177 PMCID: PMC7501955 DOI: 10.2147/dddt.s263701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 09/02/2020] [Indexed: 11/23/2022]
Abstract
Introduction Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that N-phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G). As A3G is capable of inhibiting the replication of HBV, we screened the N-phenylbenzamide derivatives against HBV. Methods In this study, a new derivative, N-(4-chlorophenyl)-4-methoxy-3-(methylamino) benzamide (IMB-0523), was synthesized and its anti-HBV activity was evaluated in vitro and in vivo. The acute toxicity and pharmacokinetic profiles of IMB-0523 were also investigated. Results Our results show that IMB-0523 has higher anti-HBV activity in both wild-type HBV (IC50: 1.99 µM) and drug-resistant HBV (IC50: 3.30 µM) than lamivudine (3TC, IC50: 7.37 µM in wild-type HBV, IC50: >440 µM in drug-resistant HBV). The antiviral effect of IMB-0523 against HBV may be due to an increased level of intracellular A3G. IMB-0523 also showed low acute toxicity (LD50: 448 mg/kg) in mice and promising PK properties (AUC0-t: 7535.10±2226.73 µg·h/L) in rats. Further, IMB-0523 showed potent anti-HBV activity in DHBV-infected ducks. Conclusion Thus, IMB-0523 may be a potential anti-HBV agent with different mechanisms than current anti-HBV treatment options.
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Affiliation(s)
- A-Long Cui
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Wen-Fang Sun
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.,CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Zhao-Jin Zhong
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Jie Jin
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Si-Tu Xue
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Shuo Wu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.,CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Yu-Huan Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.,CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Zhuo-Rong Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
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43
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Poulain F, Lejeune N, Willemart K, Gillet NA. Footprint of the host restriction factors APOBEC3 on the genome of human viruses. PLoS Pathog 2020; 16:e1008718. [PMID: 32797103 PMCID: PMC7449416 DOI: 10.1371/journal.ppat.1008718] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 08/26/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
APOBEC3 enzymes are innate immune effectors that introduce mutations into viral genomes. These enzymes are cytidine deaminases which transform cytosine into uracil. They preferentially mutate cytidine preceded by thymidine making the 5'TC motif their favored target. Viruses have evolved different strategies to evade APOBEC3 restriction. Certain viruses actively encode viral proteins antagonizing the APOBEC3s, others passively face the APOBEC3 selection pressure thanks to a depleted genome for APOBEC3-targeted motifs. Hence, the APOBEC3s left on the genome of certain viruses an evolutionary footprint. The aim of our study is the identification of these viruses having a genome shaped by the APOBEC3s. We analyzed the genome of 33,400 human viruses for the depletion of APOBEC3-favored motifs. We demonstrate that the APOBEC3 selection pressure impacts at least 22% of all currently annotated human viral species. The papillomaviridae and polyomaviridae are the most intensively footprinted families; evidencing a selection pressure acting genome-wide and on both strands. Members of the parvoviridae family are differentially targeted in term of both magnitude and localization of the footprint. Interestingly, a massive APOBEC3 footprint is present on both strands of the B19 erythroparvovirus; making this viral genome one of the most cleaned sequences for APOBEC3-favored motifs. We also identified the endemic coronaviridae as significantly footprinted. Interestingly, no such footprint has been detected on the zoonotic MERS-CoV, SARS-CoV-1 and SARS-CoV-2 coronaviruses. In addition to viruses that are footprinted genome-wide, certain viruses are footprinted only on very short sections of their genome. That is the case for the gamma-herpesviridae and adenoviridae where the footprint is localized on the lytic origins of replication. A mild footprint can also be detected on the negative strand of the reverse transcribing HIV-1, HIV-2, HTLV-1 and HBV viruses. Together, our data illustrate the extent of the APOBEC3 selection pressure on the human viruses and identify new putatively APOBEC3-targeted viruses.
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Affiliation(s)
- Florian Poulain
- Namur Research Institute for Life Sciences (NARILIS), Integrated Veterinary Research Unit (URVI), University of Namur, Namur, Belgium
| | - Noémie Lejeune
- Namur Research Institute for Life Sciences (NARILIS), Integrated Veterinary Research Unit (URVI), University of Namur, Namur, Belgium
| | - Kévin Willemart
- Namur Research Institute for Life Sciences (NARILIS), Integrated Veterinary Research Unit (URVI), University of Namur, Namur, Belgium
| | - Nicolas A. Gillet
- Namur Research Institute for Life Sciences (NARILIS), Integrated Veterinary Research Unit (URVI), University of Namur, Namur, Belgium
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44
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Sui S, Jiao Z, Chen H, Niyazi M, Wang L. Association between APOBEC3s and HPV16 E2 gene hypermutation in Uygur females with cervical cancer. Oncol Lett 2020; 20:1752-1760. [PMID: 32724418 PMCID: PMC7377173 DOI: 10.3892/ol.2020.11697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 01/15/2020] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to investigate whether apolipoprotein B mRNA-editing enzyme catalytic polypeptides (A3) are involved in the regulation of cervical cancer development and human papilloma virus (HPV)16 sustained infection in Uighur females. Cervical tissues of Uygur patients with HPV16 with cervical lesions were collected. Expression levels of A3C, A3F and A3G were detected using reverse transcription-quantitative PCR and western blotting. A model of SiHa cells with high expression levels of A3C, A3F and A3G was constructed. Hypermutation was detected using the differential DNA denaturation PCR and positive samples were amplified and sequenced. There were significant differences in A3 expression levels in cervical lesions of different grades. A3C and A3F mRNA and protein expression in cervical cancer tissues were significantly lower, whereas the A3G mRNA and protein expression levels were significantly higher compared with the cervicitis and cervical intraepithelial neoplasia (CIN) I–III groups. Hypermutation rates were increased with cervical lesion development. C>T and G>A base substitutions were detected in all hypermutation samples and numbers of C>T and G>A base substitutions in single samples in the cervical cancer group were significantly higher compared with those in the CIN I–III and cervicitis groups. Following transfection of A3F and A3G, HPV E2 mRNA and protein expression levels were significantly decreased in SiHa cells. Numerous C>T and G>A base substitutions were detected in the HPV E2 gene in A3G and A3C overexpressing SiHa cells. A3 family proteins inhibit viral replication during HPV16 infection and regulate the HPV16 integration by inducing C>T and G>A hypermutations in the HPV16 E2 gene, thus affecting the cervical cancer pathogenesis and development.
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Affiliation(s)
- Shuang Sui
- Department of Obstetrics and Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Zhen Jiao
- Department of Obstetrics and Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Hongxiang Chen
- Department of Obstetrics and Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Mayinuer Niyazi
- Department of Obstetrics and Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Lin Wang
- Department of Obstetrics and Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
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45
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Lau KCK, Joshi SS, Mahoney DJ, Mason AL, van Marle G, Osiowy C, Coffin CS. Differences in HBV Replication, APOBEC3 Family Expression, and Inflammatory Cytokine Levels Between Wild-Type HBV and Pre-core (G1896A) or Basal Core Promoter (A1762T/G1764A) Mutants. Front Microbiol 2020; 11:1653. [PMID: 32760388 PMCID: PMC7372132 DOI: 10.3389/fmicb.2020.01653] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 06/25/2020] [Indexed: 12/15/2022] Open
Abstract
Background Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) world-wide. HBV variants, particularly the G1896A pre-core (PC) and A1762T/G1764A basal core promoter (BCP) mutations, are established risk factors for cirrhosis and HCC, but the molecular biological basis is unclear. We hypothesized that these variants result in differential HBV replication, APOBEC3 family expression, and cytokine/chemokine expression. Methods HepG2 cells were transfected with monomeric full-length containing wild-type, PC, or BCP HBV. Cells and supernatant were collected to analyze viral infection markers (i.e., HBsAg, HBeAg, HBV DNA, and RNA). Cellular APOBEC3 expression and activity was assessed by quantitative real-time (qRT)-PCR, immunoblot, differential DNA denaturation PCR, and sequencing. Cytokine/chemokines in the supernatant and in serum from 11 CHB carriers (4 non-cirrhotic; 7 cirrhotic and/or HCC) with predominantly wild-type, PC, or BCP variants were evaluated by Luminex. Results HBeAg expression was reduced in PC and BCP variants, and higher supernatant HBV DNA and HBV RNA levels were found with A1762T/G1764A vs. G1896A mutant (p < 0.05). Increased APOBEC3G protein levels in wild-type vs. mutant were not associated with HBV covalently closed circular DNA G-to-A hypermutations. Differences in cytokine/chemokine expression in culture supernatants, especially IL-13 were observed amongst the variants analyzed. Noticeable increases of numerous cytokines/chemokines, including IL-4 and IL-8, were observed in ex vivo serum collected from CHB carriers with PC mutant. Conclusion HBV sequence variation leads to differences in HBV protein production (HBeAg) and viral replication in addition to altered host innate antiviral restriction factor (APOBEC3) and cytokine/chemokine expression.
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Affiliation(s)
- Keith C K Lau
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shivali S Joshi
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Douglas J Mahoney
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Andrew L Mason
- Department of Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carla Osiowy
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Winnipeg, MB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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46
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Bockmann JH, Stadler D, Xia Y, Ko C, Wettengel JM, Schulze Zur Wiesch J, Dandri M, Protzer U. Comparative Analysis of the Antiviral Effects Mediated by Type I and III Interferons in Hepatitis B Virus-Infected Hepatocytes. J Infect Dis 2020; 220:567-577. [PMID: 30923817 DOI: 10.1093/infdis/jiz143] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 03/27/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Type III interferons (IFNs) (λ1-3) activate similar signaling cascades as type I IFNs (α and β) via different receptors. Since IFN-α and lymphotoxin-β activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-β and -λ may also induce these antiviral effects in differentiated HBV-infected hepatocytes. METHODS After determining the biological activity of IFN-α2, -β1, -λ1, and -λ2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV-infected primary human hepatocytes and HepaRG cells. RESULTS Type I and III IFNs reduced nuclear open-circle DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing polymerase chain reaction and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-α, -β, and -λ-treated liver cells indicating deamination. All IFNs induced apolipoprotein B messenger RNA-editing enzyme-catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours of treatment, but IFN-β and -λ induced longer-lasting expression of APOBEC deaminases in comparison to IFN-α. CONCLUSIONS IFN-β, IFN-λ1, and IFN-λ2 induce cccDNA deamination and degradation at least as efficiently as IFN-α, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.
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Affiliation(s)
- Jan-Hendrik Bockmann
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich.,I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
| | - Daniela Stadler
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich
| | - Yuchen Xia
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich.,State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, China
| | - Chunkyu Ko
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich
| | - Jochen M Wettengel
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich
| | - Julian Schulze Zur Wiesch
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
| | - Maura Dandri
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
| | - Ulrike Protzer
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
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47
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Ni L, Li C, Li Y. Correlation of APOBEC3G expression with liver function indexes of patients with chronic hepatitis B and comparison in chronic hepatitis B, liver cirrhosis and liver cancer. Oncol Lett 2020; 19:2562-2567. [PMID: 32194760 DOI: 10.3892/ol.2020.11257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 12/05/2019] [Indexed: 01/23/2023] Open
Abstract
Correlation of APOBEC3G expression with liver function indexes of patients with chronic hepatitis B and its expression in chronic hepatitis B, liver cirrhosis and liver cancer were investigated to evaluated the significance of APOBEC3G. Fifty-eight patients with chronic hepatitis B were selected, including 20 cases of chronic hepatitis B, 19 cases of liver cirrhosis and 19 cases of liver cancer. Liver function indexes were detected and analyzed, and messenger ribonucleic acid (mRNA) and protein expression levels of APOBEC3G in liver tissues were detected via reverse transcription-polymerase chain reaction (RT-PCR), western blotting and immunohistochemistry, followed by correlation analysis. Certain liver function indexes had significant differences among the three groups of patients (P<0.05). Results of RT-PCR, Western blotting and immunohistochemistry confirmed that the content of APOBEC3G in liver tissues was the highest in patients with chronic hepatitis B, slightly lower in patients with liver cirrhosis and the lowest in patients with liver cancer. The content of APOBEC3G mRNA in liver tissues had a certain correlation with the content of alanine aminotransferase (ALT) (r2 =0.34, P<0.05). Other liver function indexes had no significant correlations with APOBEC3G (P>0.05). APOBEC3G expression has a certain correlation with some liver function indexes of patients with chronic hepatitis B. There are significant differences in the expression level of APOBEC3G in patients with hepatitis, liver cirrhosis and liver cancer.
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Affiliation(s)
- Lina Ni
- Department of Blood Transfusion, Weihai Central Hospital, Wendeng, Weihai, Shandong 264400, P.R. China
| | - Chuanbao Li
- Department of Hepatobiliary Surgery, Weihai Central Hospital, Wendeng, Weihai, Shandong 264400, P.R. China
| | - Yingbo Li
- Department of Blood Transfusion, Weihai Central Hospital, Wendeng, Weihai, Shandong 264400, P.R. China
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48
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McDaniel YZ, Wang D, Love RP, Adolph MB, Mohammadzadeh N, Chelico L, Mansky LM. Deamination hotspots among APOBEC3 family members are defined by both target site sequence context and ssDNA secondary structure. Nucleic Acids Res 2020; 48:1353-1371. [PMID: 31943071 PMCID: PMC7026630 DOI: 10.1093/nar/gkz1164] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 11/27/2019] [Accepted: 12/02/2019] [Indexed: 12/26/2022] Open
Abstract
The human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3, A3) family member proteins can deaminate cytosines in single-strand (ss) DNA, which restricts human immunodeficiency virus type 1 (HIV-1), retrotransposons, and other viruses such as hepatitis B virus, but can cause a mutator phenotype in many cancers. While structural information exists for several A3 proteins, the precise details regarding deamination target selection are not fully understood. Here, we report the first parallel, comparative analysis of site selection of A3 deamination using six of the seven purified A3 member enzymes, oligonucleotides having 5'TC3' or 5'CT3' dinucleotide target sites, and different flanking bases within diverse DNA secondary structures. A3A, A3F and A3H were observed to have strong preferences toward the TC target flanked by A or T, while all examined A3 proteins did not show a preference for a TC target flanked by a G. We observed that the TC target was strongly preferred in ssDNA regions rather than dsDNA, loop or bulge regions, with flanking bases influencing the degree of preference. CT was also shown to be a potential deamination target. Taken together, our observations provide new insights into A3 enzyme target site selection and how A3 mutagenesis impacts mutation rates.
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Affiliation(s)
- Yumeng Z McDaniel
- Veterinary Medicine Graduate Program, University of Minnesota, Minneapolis, MN 55455 USA
- Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455 USA
| | - Dake Wang
- Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455 USA
- Pharmacology Graduate Program, University of Minnesota, Minneapolis, MN 55455 USA
| | - Robin P Love
- Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Madison B Adolph
- Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Nazanin Mohammadzadeh
- Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Linda Chelico
- Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Louis M Mansky
- Veterinary Medicine Graduate Program, University of Minnesota, Minneapolis, MN 55455 USA
- Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455 USA
- Pharmacology Graduate Program, University of Minnesota, Minneapolis, MN 55455 USA
- Division of Basic Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455 USA
- Department of Microbiology & Immunology, University of Minnesota, Minneapolis, MN 55455 USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455 USA
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49
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Meng Z, Chen Y, Lu M. Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection. Front Immunol 2020; 10:3127. [PMID: 32117201 PMCID: PMC7018702 DOI: 10.3389/fimmu.2019.03127] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
“Functional cure” is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. “Functional cure” can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.
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Affiliation(s)
- Zhongji Meng
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yuanyuan Chen
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, Essen, Germany
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50
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Yang H, Ito F, Wolfe AD, Li S, Mohammadzadeh N, Love RP, Yan M, Zirkle B, Gaba A, Chelico L, Chen XS. Understanding the structural basis of HIV-1 restriction by the full length double-domain APOBEC3G. Nat Commun 2020; 11:632. [PMID: 32005813 PMCID: PMC6994475 DOI: 10.1038/s41467-020-14377-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
APOBEC3G, a member of the double-domain cytidine deaminase (CD) APOBEC, binds RNA to package into virions and restrict HIV-1 through deamination-dependent or deamination-independent inhibition. Mainly due to lack of a full-length double-domain APOBEC structure, it is unknown how CD1/CD2 domains connect and how dimerization/multimerization is linked to RNA binding and virion packaging for HIV-1 restriction. We report rhesus macaque A3G structures that show different inter-domain packing through a short linker and refolding of CD2. The A3G dimer structure has a hydrophobic dimer-interface matching with that of the previously reported CD1 structure. A3G dimerization generates a surface with intensified positive electrostatic potentials (PEP) for RNA binding and dimer stabilization. Unexpectedly, mutating the PEP surface and the hydrophobic interface of A3G does not abolish virion packaging and HIV-1 restriction. The data support a model in which only one RNA-binding mode is critical for virion packaging and restriction of HIV-1 by A3G. APOBEC3G (A3G) belongs to the DNA/RNA cytosine deaminase family that plays important roles in innate immunity against HIV and internal retroelements. Here the authors report the structures of two full-length A3G variants that provides insight into domain organization, multimerization, RNA binding, and viral restriction.
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Affiliation(s)
- Hanjing Yang
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA
| | - Fumiaki Ito
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA
| | - Aaron D Wolfe
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.,Genetic, Molecular and Cellular Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Shuxing Li
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.,Center of Excellence in NanoBiophysics, University of Southern California, Los Angeles, CA, 90089, USA
| | - Nazanin Mohammadzadeh
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Robin P Love
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Maocai Yan
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.,School of Pharmacy, Jining Medical University, 276800, Rizhao, Shandong, China
| | - Brett Zirkle
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.,Genetic, Molecular and Cellular Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Amit Gaba
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Linda Chelico
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Xiaojiang S Chen
- Molecular and Computational Biology, Departments of Biological Sciences, Chemistry, University of Southern California, Los Angeles, CA, 90089, USA. .,Genetic, Molecular and Cellular Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. .,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA. .,Center of Excellence in NanoBiophysics, University of Southern California, Los Angeles, CA, 90089, USA.
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