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1
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OuYang C, Shi H, Lin Z. Identification of Alzheimer's disease susceptibility genes by the integration of genomics and transcriptomics. Neurol Res 2025:1-13. [PMID: 40331660 DOI: 10.1080/01616412.2025.2499890] [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: 01/05/2025] [Accepted: 04/23/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND Alzheimer's disease (AD) is a progressive neurodegenerative disease. With the deepening of clinical and genomic research, a series of biomarkers and risk factors related to AD have been identified. However, the exact molecular mechanism of AD is not completely understood. METHODS By combining expression quantitative trait loci (eQTLs) analysis with the results of genome-wide association studies (GWAS), the candidate genes (CG) related to AD were screened out accurately. We identified that intersection genes of differentially expressed genes (DEGs) and CG are the key genes. Then, GO, KEGG, and GSEA were utilized for functional enrichment analysis. Finally, we predicted AD responses to immunotherapy by the single sample gene set enrichment analysis (ssGSEA). RESULTS A total of 253 DEGs were identified. The three key genes (VASP, SURF2, and TARBP1) were identified by taking the intersection of DEGs and CG. Through Mendelian randomization (MR) analysis, it was found that the risk of AD was significantly increased when VASP expression increased (OR = 0.1.046), while the risk of AD was significantly decreased when SURF2 (OR = 0.897) and TARBP1(OR = 0.920) expression increased. Subsequently, the functional analysis indicated that the core genes were mainly enriched in Leukocyte Transendothelial Migration, cGMP-PKG signaling pathway, and Rap1 signaling pathway. Through ssGSEA analysis showed that all three core genes were significantly related to M2 macrophages. CONCLUSIONS Three core genes were screened by integrating eQTLs data, GWAS data and transfer group data, and the potential mechanism of diagnosis and treatment of AD was revealed.
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Affiliation(s)
- Chenghong OuYang
- Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Hanping Shi
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Zhiying Lin
- Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
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2
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Ji M, Li L, Yu J, Wu Z, Sheng Y, Wang F. New insights into the function and therapeutic potential of RNA-binding protein TRBP in viral infection, chronic metabolic diseases, brain disorders and cancer. Life Sci 2024; 358:123159. [PMID: 39447729 DOI: 10.1016/j.lfs.2024.123159] [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: 08/20/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
RNA-binding proteins (RBPs) and non-coding RNAs are crucial trans-acting factors that bind to specific cis-acting elements in mRNAs, thereby regulating their stability and translation. The trans-activation response (TAR) RNA-binding protein (TRBP) recognizes precursor microRNAs (pre-miRNAs), modulates miRNA maturation, and influences miRNA interference (mi-RNAi) mediated by the RNA-induced silencing complex (RISC). TRBP also directly binds and mediates the degradation of certain mRNAs. Thus, TRBP acts as a hub for regulating gene expression and influences a variety of biological processes, including immune evasion, metabolic abnormalities, stress response, angiogenesis, hypoxia, and metastasis. Aberrant TRBP expression has been proven to be closely related to the initiation and progression of diseases, such as viral infection, chronic metabolic diseases, brain disorders, and cancer. This review summarizes the roles of TRBP in cancer and other diseases, the therapeutic potential of TRBP inhibition, and the current status of drug discovery on TRBP.
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Affiliation(s)
- Minghui Ji
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jialing Yu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Wu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Fei Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
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3
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Moezpoor MR, Stevenson M. Help or Hinder: Protein Host Factors That Impact HIV-1 Replication. Viruses 2024; 16:1281. [PMID: 39205255 PMCID: PMC11360189 DOI: 10.3390/v16081281] [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: 07/22/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
Interactions between human immunodeficiency virus type 1 (HIV-1) and the host factors or restriction factors of its target cells determine the cell's susceptibility to, and outcome of, infection. Factors intrinsic to the cell are involved at every step of the HIV-1 replication cycle, contributing to productive infection and replication, or severely attenuating the chances of success. Furthermore, factors unique to certain cell types contribute to the differences in infection between these cell types. Understanding the involvement of these factors in HIV-1 infection is a key requirement for the development of anti-HIV-1 therapies. As the list of factors grows, and the dynamic interactions between these factors and the virus are elucidated, comprehensive and up-to-date summaries that recount the knowledge gathered after decades of research are beneficial to the field, displaying what is known so that researchers can build off the groundwork of others to investigate what is unknown. Herein, we aim to provide a review focusing on protein host factors, both well-known and relatively new, that impact HIV-1 replication in a positive or negative manner at each stage of the replication cycle, highlighting factors unique to the various HIV-1 target cell types where appropriate.
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Affiliation(s)
- Michael Rameen Moezpoor
- Department of Microbiology and Immunology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Mario Stevenson
- Raymond F. Schinazi and Family Endowed Chair in Biomedicine; Professor of Medicine; Director, Institute of AIDS and Emerging Infectious Diseases; Department of Microbiology and Immunology, University of Miami Leonard M. Miller School of Medicine, Life Science Technology Park, 1951 NW 7th Avenue, Room 2331B, Suite 200, Miami, FL 33136, USA;
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4
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Jacobs NR, Norton PA. Role of chromosome 1q copy number variation in hepatocellular carcinoma. World J Hepatol 2021; 13:662-672. [PMID: 34239701 PMCID: PMC8239492 DOI: 10.4254/wjh.v13.i6.662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/13/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Chromosome 1q often has been observed to be amplified in hepatocellular carcinoma. This review summarizes literature reports of multiple genes that have been proposed as possible 1q amplification drivers. These largely fall within 1q21-1q23. In addition, publicly available copy number alteration data from The Cancer Genome Atlas project were used to identify additional candidate genes involved in carcinogenesis. The most frequent location for gene amplification was 1q22, consistent with the results of the literature search. The genes TPM3 and NUF2 were found to be candidates whose amplification and/or mRNA up-regulation was most highly associated with poorer hepatocellular carcinoma outcomes.
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Affiliation(s)
- Nathan R Jacobs
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
| | - Pamela A Norton
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
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5
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Expression profiling of human milk derived exosomal microRNAs and their targets in HIV-1 infected mothers. Sci Rep 2020; 10:12931. [PMID: 32737406 PMCID: PMC7395778 DOI: 10.1038/s41598-020-69799-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 07/16/2020] [Indexed: 12/21/2022] Open
Abstract
Despite the use of antiretroviral therapy (ART) in HIV-1 infected mothers approximately 5% of new HIV-1 infections still occur in breastfed infants annually, which warrants for the development of novel strategies to prevent new HIV-1 infections in infants. Human milk (HM) exosomes are highly enriched in microRNAs (miRNAs), which play an important role in neonatal immunity. Furthermore, HM exosomes from healthy donors are known to inhibit HIV-1 infection and transmission; however, the effect of HIV-1 on HM exosomal miRNA signatures remains unknown. In this study, we used nCounter NanoString technology and investigated miRNAs expression profiles in first week postpartum HM exosomes from HIV-1 infected and uninfected control mothers (n = 36). Our results indicated that HIV-1 perturbed the differential expression patterns of 19 miRNAs (13 upregulated and 6 downregulated) in HIV-1 infected women compared to healthy controls. DIANA-miR functional pathway analyses revealed that multiple biological pathways are involved including cell cycle, pathways in cancer, TGF-β signaling, FoxO signaling, fatty acid biosynthesis, p53 signaling and apoptosis. Moreover, the receiver operating characteristics (ROC) curve analyses of miR-630 and miR-378g yielded areas under the ROC curves of 0.82 (95% CI 0.67 to 0.82) and 0.83 (95% CI 0.67 to 0.83), respectively highlighting their potential to serve as biomarkers to identify HIV-1 infection in women. These data may contribute to the development of new therapeutic strategies in prevention of mother-to-child transmission (MTCT) of HIV-1.
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Shedding Light on the Role of Extracellular Vesicles in HIV Infection and Wound Healing. Viruses 2020; 12:v12060584. [PMID: 32471020 PMCID: PMC7354510 DOI: 10.3390/v12060584] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/19/2020] [Accepted: 05/25/2020] [Indexed: 12/18/2022] Open
Abstract
Extracellular vesicles (EVs) play an important role in intercellular communication. They are naturally released from cells into the extracellular environment. Based on their biogenesis, release pathways, size, content, and function, EVs are classified into exosomes, microvesicles (MVs), and apoptotic bodies (ApoBDs). Previous research has documented that EVs, specifically exosomes and MVs, play an important role in HIV infection, either by promoting HIV infection and pathogenesis or by inhibiting HIV-1 to a certain extent. We have also previously reported that EVs (particularly exosomes) from vaginal fluids inhibit HIV at the post-entry step (i.e., reverse transcription, integration). Besides the role that EVs play in HIV, they are also known to regulate the process of wound healing by regulating both the immune and inflammatory responses. It is noted that during the advanced stages of HIV infection, patients are at greater risk of wound-healing and wound-related complications. Despite ongoing research, the data on the actual effects of EVs in HIV infection and wound healing are still premature. This review aimed to update the current knowledge about the roles of EVs in regulating HIV pathogenesis and wound healing. Additionally, we highlighted several avenues of EV involvement in the process of wound healing, including coagulation, inflammation, proliferation, and extracellular matrix remodeling. Understanding the role of EVs in HIV infection and wound healing could significantly contribute to the development of new and potent antiviral therapeutic strategies and approaches to resolve impaired wounds in HIV patients.
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7
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Gonelli CA, Khoury G, Center RJ, Purcell DFJ. HIV-1-based Virus-like Particles that Morphologically Resemble Mature, Infectious HIV-1 Virions. Viruses 2019; 11:v11060507. [PMID: 31159488 PMCID: PMC6630479 DOI: 10.3390/v11060507] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/23/2019] [Accepted: 05/29/2019] [Indexed: 01/04/2023] Open
Abstract
A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-structured, virion-associated Env to elicit bNAbs, and also stimulate T cell responses. Here, we optimize our DNA vaccine plasmids as VLP expression vectors for efficient Env incorporation and budding. The original vector that was used in human trials inefficiently produced VLPs, but maximized safety by inactivating RNA genome packaging, enzyme functions that are required for integration into the host genome, and deleting accessory proteins Vif, Vpr, and Nef. These original DNA vaccine vectors generated VLPs with incomplete protease-mediated cleavage of Gag and were irregularly sized. Mutations to restore function within the defective genes revealed that several of the reverse transcriptase (RT) deletions mediated this immature phenotype. Here, we made efficient budding, protease-processed, and mature-form VLPs that resembled infectious virions by introducing alternative mutations that completely removed the RT domain, but preserved most other safety mutations. These VLPs, either expressed from DNA vectors in vivo or purified after expression in vitro, are potentially useful immunogens that can be used to elicit antibody responses that target Env on fully infectious HIV-1 virions.
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Affiliation(s)
- Christopher A Gonelli
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
| | - Georges Khoury
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
| | - Rob J Center
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
- Viral Entry and Vaccines Laboratory, Disease Elimination, Burnet Institute, Melbourne, Victoria 3004, Australia.
| | - Damian F J Purcell
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
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8
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Ye J, Wang J, Zhang N, Liu Y, Tan L, Xu L. Expression of TARBP1 protein in human non-small-cell lung cancer and its prognostic significance. Oncol Lett 2018; 15:7182-7190. [PMID: 29731880 PMCID: PMC5920659 DOI: 10.3892/ol.2018.8202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 02/27/2018] [Indexed: 12/22/2022] Open
Abstract
The aim of the present study was to investigate the expression of transactivation response RNA-binding protein (TARBP)1 and its clinical significance in human non-small-cell lung cancer (NSCLC). TARBP1 expression at the mRNA level was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 NSCLC tissues and paired adjacent normal tissues. TARBP1 protein expression was analyzed in 90 paraffin-embedded NSCLC tissue samples and paired adjacent normal tissues by immunohistochemistry. Statistical analyses were performed to assess the clinicopathological significance of TARBP1 expression. The expression of TARBP1 mRNA was higher in the 10 NSCLC samples than in the paired adjacent non-tumor tissues (P=0.0017). In the paraffin-embedded tissue samples, the expression level of TARBP1 was higher in the cancer tissues than in the adjacent non-cancerous tissues. TARBP1 expression was detected in 76.67% (69/90) of the NSCLC samples and in 22.22% (20/90) of the adjacent normal lung tissues (P<0.001). The expression of TARBP1 was significantly associated with histological grade (P<0.001), clinical stage (P=0.024) and pathological type (P<0.001), along with a decreased overall survival (OS) rate (P<0.001). On multivariate analysis, the expression of TARBP1 was an independent prognostic factor for hazard ratio (OS, 2.729; 95% confidence interval, 1.471-5.061; P=0.003). TARBP1 is overexpressed in NSCLC, and the expression of TARBP1 is associated with pathological grade, clinical stage and pathological type. Thus, TARBP1 may be an independent prognostic marker in patients with NSCLC.
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Affiliation(s)
- Jingmei Ye
- Department of Blood Transfusion, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510230, P.R. China
| | - Jiani Wang
- Breast Cancer Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Nana Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yu Liu
- Breast Cancer Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Li Tan
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510230, P.R. China
| | - Lihua Xu
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510230, P.R. China.,Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510230, P.R. China
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9
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Multiple Inhibitory Factors Act in the Late Phase of HIV-1 Replication: a Systematic Review of the Literature. Microbiol Mol Biol Rev 2018; 82:82/1/e00051-17. [PMID: 29321222 DOI: 10.1128/mmbr.00051-17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The use of lentiviral vectors for therapeutic purposes has shown promising results in clinical trials. The ability to produce a clinical-grade vector at high yields remains a critical issue. One possible obstacle could be cellular factors known to inhibit human immunodeficiency virus (HIV). To date, five HIV restriction factors have been identified, although it is likely that more factors are involved in the complex HIV-cell interaction. Inhibitory factors that have an adverse effect but do not abolish virus production are much less well described. Therefore, a gap exists in the knowledge of inhibitory factors acting late in the HIV life cycle (from transcription to infection of a new cell), which are relevant to the lentiviral vector production process. The objective was to review the HIV literature to identify cellular factors previously implicated as inhibitors of the late stages of lentivirus production. A search for publications was conducted on MEDLINE via the PubMed interface, using the keyword sequence "HIV restriction factor" or "HIV restriction" or "inhibit HIV" or "repress HIV" or "restrict HIV" or "suppress HIV" or "block HIV," with a publication date up to 31 December 2016. Cited papers from the identified records were investigated, and additional database searches were performed. A total of 260 candidate inhibitory factors were identified. These factors have been identified in the literature as having a negative impact on HIV replication. This study identified hundreds of candidate inhibitory factors for which the impact of modulating their expression in lentiviral vector production could be beneficial.
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10
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Kwarteng A, Ahuno ST, Kwakye-Nuako G. The therapeutic landscape of HIV-1 via genome editing. AIDS Res Ther 2017; 14:32. [PMID: 28705213 PMCID: PMC5513397 DOI: 10.1186/s12981-017-0157-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 05/30/2017] [Indexed: 12/31/2022] Open
Abstract
Current treatment for HIV-1 largely relies on chemotherapy through the administration of antiretroviral drugs. While the search for anti-HIV-1 vaccine remain elusive, the use of highly active antiretroviral therapies (HAART) have been far-reaching and has changed HIV-1 into a manageable chronic infection. There is compelling evidence, including several side-effects of ARTs, suggesting that eradication of HIV-1 cannot depend solely on antiretrovirals. Gene therapy, an expanding treatment strategy, using RNA interference (RNAi) and programmable nucleases such as meganuclease, zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins (CRISPR-Cas9) are transforming the therapeutic landscape of HIV-1. TALENS and ZFNS are structurally similar modular systems, which consist of a FokI endonuclease fused to custom-designed effector proteins but have been largely limited, particularly ZFNs, due to their complexity and cost of protein engineering. However, the newly developed CRISPR-Cas9 system, consists of a single guide RNA (sgRNA), which directs a Cas9 endonuclease to complementary target sites, and serves as a superior alternative to the previous protein-based systems. The techniques have been successfully applied to the development of better HIV-1 models, generation of protective mutations in endogenous/host cells, disruption of HIV-1 genomes and even reactivating latent viruses for better detection and clearance by host immune response. Here, we focus on gene editing-based HIV-1 treatment and research in addition to providing perspectives for refining these techniques.
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Affiliation(s)
- Alexander Kwarteng
- Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology (KNUST), PMB, Kumasi, Ghana
- Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana
| | - Samuel Terkper Ahuno
- Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology (KNUST), PMB, Kumasi, Ghana
| | - Godwin Kwakye-Nuako
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
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11
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MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection. J Virol 2017; 91:JVI.02048-16. [PMID: 28250134 DOI: 10.1128/jvi.02048-16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 02/24/2017] [Indexed: 02/02/2023] Open
Abstract
Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miRNA miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.IMPORTANCE Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/Toll-like receptor 4/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.
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Nejati A, Shahmahmoodi S, Arefian E, Shoja Z, Marashi SM, Tabatabaie H, Mollaei-Kandelous Y, Soleimani M, Nategh R. Efficient inhibition of human immunodeficiency virus replication using novel modified microRNA-30a targeting 3'-untranslated region transcripts. Exp Ther Med 2016; 11:1833-1838. [PMID: 27168813 PMCID: PMC4840495 DOI: 10.3892/etm.2016.3121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 12/22/2015] [Indexed: 12/15/2022] Open
Abstract
RNA interference (RNAi)-based gene therapy is currently considered to be a combinatorial anti-human immunodeficiency virus-1 (HIV-1) therapy. Although artificial polycistronic microRNAs (miRs) can reduce HIV-1 escape mutant variants, this approach may increase the risk of side effects. The present study aimed to optimize the efficiency of anti-HIV RNAi gene therapy in order to reduce the cell toxicity induced by multi-short hairpin RNA expression. An artificial miR-30a-3'-untranslated region (miR-3-UTR) obtained from a single RNA polymerase II was used to simultaneously target all viral transcripts. The results of the present study demonstrated that HIV-1 replication was significantly inhibited in the cells with the miR-3-UTR construct, suggesting that miR-3'-UTR may serve as a promising tool for RNAi-based gene therapy in the treatment of HIV-1.
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Affiliation(s)
- Ahmad Nejati
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14716-13151, Iran
| | - Shohreh Shahmahmoodi
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14716-13151, Iran
| | - Ehsan Arefian
- Biotechnology Center, College of Science, University of Tehran, Tehran 14176-14411, Iran; Department of Molecular Biology and Genetic Engineering, Stem Cell Technology Research Center, Tehran 19977-75555, Iran
| | - Zabihollah Shoja
- Virology Department, Pasteur Institute of Iran, Tehran 13169-43551, Iran
| | - Sayed-Mahdi Marashi
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14716-13151, Iran
| | - Hamideh Tabatabaie
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14716-13151, Iran
| | | | - Masoud Soleimani
- Department of Molecular Biology and Genetic Engineering, Stem Cell Technology Research Center, Tehran 19977-75555, Iran; Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran
| | - Rakhshandeh Nategh
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14716-13151, Iran
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Daniels SM, Sinck L, Ward NJ, Melendez-Peña CE, Scarborough RJ, Azar I, Rance E, Daher A, Pang KM, Rossi JJ, Gatignol A. HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs. RNA Biol 2015; 12:123-35. [PMID: 25668122 DOI: 10.1080/15476286.2015.1014759] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Several proteins and RNAs expressed by mammalian viruses have been reported to interfere with RNA interference (RNAi) activity. We investigated the ability of the HIV-1-encoded RNA elements Trans-Activation Response (TAR) and Rev-Response Element (RRE) to alter RNAi. MicroRNA let7-based assays showed that RRE is a potent suppressor of RNAi activity, while TAR displayed moderate RNAi suppression. We demonstrate that RRE binds to TAR-RNA Binding Protein (TRBP), an essential component of the RNA Induced Silencing Complex (RISC). The binding of TAR and RRE to TRBP displaces small interfering (si)RNAs from binding to TRBP. Several stem-deleted RRE mutants lost their ability to suppress RNAi activity, which correlated with a reduced ability to compete with siRNA-TRBP binding. A lentiviral vector expressing TAR and RRE restricted RNAi, but RNAi was restored when Rev or GagPol were coexpressed. Adenoviruses are restricted by RNAi and encode their own suppressors of RNAi, the Virus-Associated (VA) RNA elements. RRE enhanced the replication of wild-type and VA-deficient adenovirus. Our work describes RRE as a novel suppressor of RNAi that acts by competing with siRNAs rather than by disrupting the RISC. This function is masked in lentiviral vectors co-expressed with viral proteins and thus will not affect their use in gene therapy. The potent RNAi suppressive effects of RRE identified in this study could be used to enhance the expression of RNAi restricted viruses used in oncolysis such as adenoviruses.
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Key Words
- Ago2, Argonaute-2
- EGFP, enhanced green fluorescent protein
- EMSA, electrophoresis mobility shift assay
- FL, firefly luciferase
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- HIV, human immunodeficiency virus
- HIV-1
- IP, immunoprecipitation
- NC, nucleocapsid
- PAGE, polyacrylamide gel electrophoresis
- RISC, RNA-Induced Silencing Complex
- RL, Renilla luciferase
- RNA interference
- RNA silencing suppressor
- RNAi, RNA interference
- RRE, Rev Response Element
- RSS, RNA silencing suppressor
- RT, reverse transcription
- Rev-Response Element RNA
- TAR RNA Binding Protein (TRBP)
- TAR, trans-activation responsive element
- TRBP, TAR RNA Binding Protein
- Trans-Activation Response Element
- UTR, untranslated region
- VA, virus-associated
- WT, wild-type
- adenovirus
- ds, double-stranded
- lentiviral vectors
- miRNA, micro RNA
- pre-miRNA, precursor miRNA
- siRNA, small interfering RNA
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Affiliation(s)
- Sylvanne M Daniels
- a Virus-Cell Interactions Laboratory ; Lady Davis Institute for Medical Research ; Montréal , Québec , Canada
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14
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Novel RNA Duplex Locks HIV-1 in a Latent State via Chromatin-mediated Transcriptional Silencing. MOLECULAR THERAPY. NUCLEIC ACIDS 2015; 4:e261. [PMID: 26506039 PMCID: PMC4881759 DOI: 10.1038/mtna.2015.31] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 08/17/2015] [Indexed: 11/18/2022]
Abstract
Transcriptional gene silencing (TGS) of mammalian genes can be induced by short interfering RNA (siRNA) targeting promoter regions. We previously reported potent TGS of HIV-1 by siRNA (PromA), which targets tandem NF-κB motifs within the viral 5′LTR. In this study, we screened a siRNA panel with the aim of identifying novel 5′LTR targets, to provide multiplexing potential with enhanced viral silencing and application toward developing alternate therapeutic strategies. Systematic examination identified a novel siRNA target, si143, confirmed to induce TGS as the silencing mechanism. TGS was prolonged with virus suppression >12 days, despite a limited ability to induce post- TGS. Epigenetic changes associated with silencing were suggested by partial reversal by histone deacetylase inhibitors and confirmed by chromatin immunoprecipitation analyses, which showed induction of H3K27me3 and H3K9me3, reduction in H3K9Ac, and recruitment of argonaute-1, all characteristic marks of heterochromatin and TGS. Together, these epigenetic changes mimic those associated with HIV-1 latency. Further, robust resistance to reactivation was observed in the J-Lat 9.2 cell latency model, when transduced with shPromA and/or sh143. These data support si/shRNA-mediated TGS approaches to HIV-1 and provide alternate targets to pursue a functional cure, whereby the viral reservoir is locked in latency following antiretroviral therapy cessation.
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15
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Ye J, Wang J, Tan L, Yang S, Xu L, Wu X, Deng H, Tan H. Expression of protein TARBP1 in human hepatocellular carcinoma and its prognostic significance. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:9089-9096. [PMID: 26464651 PMCID: PMC4583883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 07/24/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE The objective of this study was to analyze the expression of TARBP1 and its clinical significance in hepatocellular carcinoma (HCC). MATERIALS AND METHODS 90 patients with primary hepatocellular carcinoma were included in this study. The tumor and paired adjacent non-tumor tissues were collected. TARBP1 expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry. Associations of TARBP1 expression with the clinicopathological features were analyzed, and prognosis of HCC patients was evaluated. RESULTS The result show the expression of TARBP1 mRNA in liver cancer tissues were higher than in the adjacent normal liver tissues in 10 paired samples (P=0.0015). Compared with adjacent normal liver tissues, overexpression of TARBP1 was detected in 61.1% (55/90) HCC patients. TARBP1 expression was associated with the AJCC tumor stage (P=0.004) and clinical stage (P=0.005), and decreased overall survival (P=0.002). In multivariate analysis, TARBP1 expression was an independent prognostic factor for overall survival (Hazard ratio [HR]=2.773, 95% confidence interval [CI] 1.542-4.985; P=0.019). CONCLUSIONS TARBP1 is up-regulated in HCC, and the expression of TARBP1 was associated with the pathological grading and clinical stage. TARBP1 maybe is an independent prognostic marker of HCC patients.
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Affiliation(s)
- Jingmei Ye
- Department of Blood Transfusion, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230, China
| | - Jiani Wang
- Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630, China
| | - Li Tan
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230, China
| | - Shaojiang Yang
- Department of Hematology, The First People’s Hospital of FoshanFoshan 528000, China
| | - Lihua Xu
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230, China
| | - Xiaohong Wu
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230, China
| | - Huaifu Deng
- PET/CT Center, Department of Nuclear Medicine, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230, China
| | - Huo Tan
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230, China
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16
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Bobbin ML, Burnett JC, Rossi JJ. RNA interference approaches for treatment of HIV-1 infection. Genome Med 2015; 7:50. [PMID: 26019725 PMCID: PMC4445287 DOI: 10.1186/s13073-015-0174-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 05/13/2015] [Indexed: 01/05/2023] Open
Abstract
HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery.
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Affiliation(s)
- Maggie L Bobbin
- Irell & Manella School of Biological Sciences, Beckman Research Institute of City of Hope, East Duarte Road, Duarte, CA 91010 USA
| | - John C Burnett
- Irell & Manella School of Biological Sciences, Beckman Research Institute of City of Hope, East Duarte Road, Duarte, CA 91010 USA ; Department of Molecular and Cell Biology, Beckman Research Institute of City of Hope, East Duarte Road, Duarte, CA 9101 USA
| | - John J Rossi
- Irell & Manella School of Biological Sciences, Beckman Research Institute of City of Hope, East Duarte Road, Duarte, CA 91010 USA ; Department of Molecular and Cell Biology, Beckman Research Institute of City of Hope, East Duarte Road, Duarte, CA 9101 USA
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17
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Burugu S, Daher A, Meurs EF, Gatignol A. HIV-1 translation and its regulation by cellular factors PKR and PACT. Virus Res 2014; 193:65-77. [PMID: 25064266 DOI: 10.1016/j.virusres.2014.07.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 07/13/2014] [Accepted: 07/14/2014] [Indexed: 12/24/2022]
Abstract
The synthesis of proteins from viral mRNA is the first step towards viral assembly. Viruses are dependent upon the cellular translation machinery to synthesize their own proteins. The synthesis of proteins from the human immunodeficiency virus (HIV) type 1 and 2 RNAs utilize several alternative mechanisms. The regulation of viral protein production requires a constant interplay between viral requirements and the cell response to viral infection. Among the antiviral cell responses, the interferon-induced RNA activated protein kinase, PKR, regulates the cellular and viral translation. During HIV-1 infection, PKR activation is highly regulated by viral and cellular factors. The cellular TAR RNA Binding Protein, TRBP, the Adenosine Deaminase acting on RNA, ADAR1, and the PKR Activator, PACT, play important roles. Recent data show that PACT changes its function from activator to inhibitor in HIV-1 infected cells. Therefore, HIV-1 has evolved to replicate in cells in which TRBP, ADAR1 and PACT prevent PKR activation to allow efficient viral protein synthesis. This proper translation will initiate the assembly of viral particles.
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Affiliation(s)
- Samantha Burugu
- Virus-cell Interactions Laboratory, Lady Davis Institute for Medical Research, Montréal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
| | - Aïcha Daher
- Virus-cell Interactions Laboratory, Lady Davis Institute for Medical Research, Montréal, QC, Canada
| | - Eliane F Meurs
- Institut Pasteur, Department of Virology, Hepacivirus and Innate Immunity Unit, Paris, France
| | - Anne Gatignol
- Virus-cell Interactions Laboratory, Lady Davis Institute for Medical Research, Montréal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
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18
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Proteome analysis of the HIV-1 Gag interactome. Virology 2014; 460-461:194-206. [PMID: 25010285 DOI: 10.1016/j.virol.2014.04.038] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 02/06/2014] [Accepted: 04/19/2014] [Indexed: 11/22/2022]
Abstract
Human immunodeficiency virus Gag drives assembly of virions in infected cells and interacts with host factors which facilitate or restrict viral replication. Although several Gag-binding proteins have been characterized, understanding of virus-host interactions remains incomplete. In a series of six affinity purification screens, we have identified protein candidates for interaction with HIV-1 Gag. Proteins previously found in virions or identified in siRNA screens for host factors influencing HIV-1 replication were recovered. Helicases, translation factors, cytoskeletal and motor proteins, factors involved in RNA degradation and RNA interference were enriched in the interaction data. Cellular networks of cytoskeleton, SR proteins and tRNA synthetases were identified. Most prominently, components of cytoplasmic RNA transport granules were co-purified with Gag. This study provides a survey of known Gag-host interactions and identifies novel Gag binding candidates. These factors are associated with distinct molecular functions and cellular pathways relevant in host-pathogen interactions.
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19
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Huang JT, Wang J, Srivastava V, Sen S, Liu SM. MicroRNA Machinery Genes as Novel Biomarkers for Cancer. Front Oncol 2014; 4:113. [PMID: 24904827 PMCID: PMC4032885 DOI: 10.3389/fonc.2014.00113] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 05/01/2014] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs (miRNAs) directly and indirectly affect tumorigenesis. To be able to perform their myriad roles, miRNA machinery genes, such as Drosha, DGCR8, Dicer1, XPO5, TRBP, and AGO2, must generate precise miRNAs. These genes have specific expression patterns, protein-binding partners, and biochemical capabilities in different cancers. Our preliminary analysis of data from The Cancer Genome Atlas consortium on multiple types of cancer revealed significant alterations in these miRNA machinery genes. Here, we review their biological structures and functions with an eye toward understanding how they could serve as cancer biomarkers.
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Affiliation(s)
- Jing-Tao Huang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jin Wang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vibhuti Srivastava
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Subrata Sen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Song-Mei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
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20
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Swaminathan G, Navas-Martín S, Martín-García J. MicroRNAs and HIV-1 infection: antiviral activities and beyond. J Mol Biol 2013; 426:1178-97. [PMID: 24370931 DOI: 10.1016/j.jmb.2013.12.017] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 12/03/2013] [Accepted: 12/17/2013] [Indexed: 02/07/2023]
Abstract
Cellular microRNAs (miRNAs) are an important class of small, non-coding RNAs that bind to host mRNAs based on sequence complementarity and regulate protein expression. They play important roles in controlling key cellular processes including cellular inception, differentiation and death. While several viruses have been shown to encode for viral miRNAs, controversy persists over the expression of a functional miRNA encoded in the human immunodeficiency virus type 1 (HIV-1) genome. However, it has been reported that HIV-1 infectivity is influenced by cellular miRNAs. Either through directly targeting the viral genome or by targeting host cellular proteins required for successful virus replication, multiple cellular miRNAs seem to modulate HIV-1 infection and replication. Perhaps as a survival strategy, HIV-1 may modulate proteins in the miRNA biogenesis pathway to subvert miRNA-induced antiviral effects. Global expression profiles of cellular miRNAs have also identified alterations of specific miRNAs post-HIV-1 infection both in vitro and in vivo (in various infected patient cohorts), suggesting potential roles for miRNAs in pathogenesis and disease progression. However, little attention has been devoted in understanding the roles played by these miRNAs at a cellular level. In this manuscript, we review past and current findings pertaining to the field of miRNA and HIV-1 interplay. In addition, we suggest strategies to exploit miRNAs therapeutically for curbing HIV-1 infectivity, replication and latency since they hold an untapped potential that deserves further investigation.
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Affiliation(s)
- Gokul Swaminathan
- Graduate Program in Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
| | - Sonia Navas-Martín
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
| | - Julio Martín-García
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
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21
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Clerzius G, Shaw E, Daher A, Burugu S, Gélinas JF, Ear T, Sinck L, Routy JP, Mouland AJ, Patel RC, Gatignol A. The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication. Retrovirology 2013; 10:96. [PMID: 24020926 PMCID: PMC3848765 DOI: 10.1186/1742-4690-10-96] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 09/06/2013] [Indexed: 11/29/2022] Open
Abstract
Background HIV-1 translation is modulated by the activation of the interferon (IFN)-inducible Protein Kinase RNA-activated (PKR). PKR phosphorylates its downstream targets, including the alpha subunit of the eukaryotic translation Initiation Factor 2 (eIF2α), which decreases viral replication. The PKR Activator (PACT) is known to activate PKR after a cellular stress. In lymphocytic cell lines, HIV-1 activates PKR only transiently and not when cells replicate the virus at high levels. The regulation of this activation is due to a combination of viral and cellular factors that have been only partially identified. Results PKR is transiently induced and activated in peripheral blood mononuclear cells after HIV-1 infection. The addition of IFN reduces viral replication, and induces both the production and phosphorylation of PKR. In lymphocytic Jurkat cells infected by HIV-1, a multiprotein complex around PKR contains the double-stranded RNA binding proteins (dsRBPs), adenosine deaminase acting on RNA (ADAR)1 and PACT. In HEK 293T cells transfected with an HIV-1 molecular clone, PACT unexpectedly inhibited PKR and eIF2α phosphorylation and increased HIV-1 protein expression and virion production in the presence of either endogenous PKR alone or overexpressed PKR. The comparison between different dsRBPs showed that ADAR1, TAR RNA Binding Protein (TRBP) and PACT inhibit PKR and eIF2α phosphorylation in HIV-infected cells, whereas Staufen1 did not. Individual or a combination of short hairpin RNAs against PACT or ADAR1 decreased HIV-1 protein expression. In the astrocytic cell line U251MG, which weakly expresses TRBP, PACT mediated an increased HIV-1 protein expression and a decreased PKR phosphorylation. In these cells, a truncated PACT, which constitutively activates PKR in non-infected cells showed no activity on either PKR or HIV-1 protein expression. Finally, PACT and ADAR1 interact with each other in the absence of RNAs. Conclusion In contrast to its previously described activity, PACT contributes to PKR dephosphorylation during HIV-1 replication. This activity is in addition to its heterodimer formation with TRBP and could be due to its binding to ADAR1. HIV-1 has evolved to replicate in cells with high levels of TRBP, to induce the expression of ADAR1 and to change the function of PACT for PKR inhibition and increased replication.
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Affiliation(s)
- Guerline Clerzius
- Lady Davis Institute for Medical Research, 3999 Côte Ste Catherine, Montréal, QC H3T 1E2, Canada.
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22
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Aqil M, Naqvi AR, Bano AS, Jameel S. The HIV-1 Nef protein binds argonaute-2 and functions as a viral suppressor of RNA interference. PLoS One 2013; 8:e74472. [PMID: 24023945 PMCID: PMC3762824 DOI: 10.1371/journal.pone.0074472] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 08/01/2013] [Indexed: 11/21/2022] Open
Abstract
The HIV-1 accessory protein Nef is an important virulence factor. It associates with cellular membranes and modulates the endocytic machinery and signaling pathways. Nef also increases the proliferation of multivesicular bodies (MVBs), which are sites for virus assembly and budding in macrophages. The RNA interference (RNAi) pathway proteins Ago2 and GW182 localize to MVBs, suggesting these to be sites for assembly and turnover of the miRNA-induced silencing complex (miRISC). While RNAi affects HIV replication, it is not clear if the virus encodes a suppressor activity to overcome this innate host response. Here we show that Nef colocalizes with MVBs and binds Ago2 through two highly conserved Glycine-Tryptophan (GW) motifs, mutations in which abolish Nef binding to Ago2 and reduce virus yield and infectivity. Nef also inhibits the slicing activity of Ago2 and disturbs the sorting of GW182 into exosomes resulting in the suppression of miRNA-induced silencing. Thus, besides its other activities, the HIV-1 Nef protein is also proposed to function as a viral suppressor of RNAi (VSR).
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Affiliation(s)
- Madeeha Aqil
- International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India
| | - Afsar Raza Naqvi
- International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India
| | - Aalia Shahr Bano
- International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India
| | - Shahid Jameel
- International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India
- * E-mail:
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23
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Iordanskiy S, Santos S, Bukrinsky M. Nature, nurture and HIV: The effect of producer cell on viral physiology. Virology 2013; 443:208-13. [PMID: 23747196 DOI: 10.1016/j.virol.2013.05.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/23/2013] [Accepted: 05/15/2013] [Indexed: 01/13/2023]
Abstract
Macrophages and CD4-positive T lymphocytes are the major targets and producers of HIV-1. While the molecular details underlying HIV replication in macrophages and T cells become better understood, it remains unclear whether viruses produced by these target cells differ in their biological properties. Recent reports suggest that HIV virions incorporate a large number of producer cell proteins and lipids which have an effect on subsequent viral replication in newly infected cells. The identity and abundance of these incorporated factors varies between different types of producer cells, suggesting that they may influence the replication capacity and pathogenic activity of the virions produced by T cells and macrophages.
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Affiliation(s)
- Sergey Iordanskiy
- Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, George Washington University, 2300 I Street NW, Ross Hall, Washington, DC 20037, USA.
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24
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Pouliot LM, Shen DW, Suzuki T, Hall MD, Gottesman MM. Contributions of microRNA dysregulation to cisplatin resistance in adenocarcinoma cells. Exp Cell Res 2013; 319:566-74. [PMID: 23137650 PMCID: PMC3563763 DOI: 10.1016/j.yexcr.2012.10.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 10/22/2012] [Accepted: 10/30/2012] [Indexed: 01/08/2023]
Abstract
Cisplatin resistance in cancer cells is due to a pleiotropic phenotype transition that allows cells to resist cell death. miRNAs have been shown to be reliable markers of phenotype, critical in cell differentiation, and dysregulated in cancer and other pathologies. Here we investigate the influence of miRNA on cisplatin resistance in KB adenocarcinoma cells. Silencing both DICER and TRBP2 in the miRNA biosynthesis pathway in KB-3-1 (sensitive parental), KB-CP.5 (cisplatin-resistant), and KB-CP20 (highly cisplatin-resistant) cells resulted in the reversal of cisplatin resistance, with no effect on cell viability in the absence of cisplatin. We found miR-181 expression differences in the cell lines using RT-PCR, with several members of the miR-181 family overexpressed in two KB cisplatin-resistant lines and in two cisplatin-resistant lung cancer lines, compared to their respective parental cells. Functional assays showed minimal effects of miR-181 on cisplatin resistance. We conclude that the miRNA biosynthesis pathway is critical for maintaining the cisplatin-resistant phenotype, but that it is difficult to determine the precise miRNAs involved in cisplatin resistance simply using expression profiles of individual miRNA species. Functional assays are needed to determine the influence of a specific miRNA and different members of the same miRNA family may have opposite effects.
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Affiliation(s)
- Lynn M. Pouliot
- Department of Microbiology and Immunology, Georgetown University, Washington, D.C., USA
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ding-Wu Shen
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Toshihiro Suzuki
- Department of Analytical Biochemistry, Meiji Pharmaceutical University, Tokyo, Japan
| | - Matthew D. Hall
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michael M. Gottesman
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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25
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The multiple functions of TRBP, at the hub of cell responses to viruses, stress, and cancer. Microbiol Mol Biol Rev 2013; 76:652-66. [PMID: 22933564 DOI: 10.1128/mmbr.00012-12] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The TAR RNA binding protein (TRBP) has emerged as a key player in many cellular processes. First identified as a cellular protein that facilitates the replication of human immunodeficiency virus, TRBP has since been shown to inhibit the activation of protein kinase R (PKR), a protein involved in innate immune responses and the cellular response to stress. It also binds to the PKR activator PACT and regulates its function. TRBP also contributes to RNA interference as an integral part of the minimal RNA-induced silencing complex with Dicer and Argonaute proteins. Due to its multiple functions in the cell, TRBP is involved in oncogenesis when its sequence is mutated or its expression is deregulated. The depletion or overexpression of TRBP results in malignancy, suggesting that the balance of TRBP expression is key to normal cellular function. These studies show that TRBP is multifunctional and mediates cross talk between different pathways. Its activities at the molecular level impact the cellular function from normal development to cancer and the response to infections.
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Abstract
The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long-lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs.
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27
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Dahiya S, Nonnemacher MR, Wigdahl B. Deployment of the human immunodeficiency virus type 1 protein arsenal: combating the host to enhance viral transcription and providing targets for therapeutic development. J Gen Virol 2012; 93:1151-1172. [PMID: 22422068 DOI: 10.1099/vir.0.041186-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Despite the success of highly active antiretroviral therapy in combating human immunodeficiency virus type 1 (HIV-1) infection, the virus still persists in viral reservoirs, often in a state of transcriptional silence. This review focuses on the HIV-1 protein and regulatory machinery and how expanding knowledge of the function of individual HIV-1-coded proteins has provided valuable insights into understanding HIV transcriptional regulation in selected susceptible cell types. Historically, Tat has been the most studied primary transactivator protein, but emerging knowledge of HIV-1 transcriptional regulation in cells of the monocyte-macrophage lineage has more recently established that a number of the HIV-1 accessory proteins like Vpr may directly or indirectly regulate the transcriptional process. The viral proteins Nef and matrix play important roles in modulating the cellular activation pathways to facilitate viral replication. These observations highlight the cross talk between the HIV-1 transcriptional machinery and cellular activation pathways. The review also discusses the proposed transcriptional regulation mechanisms that intersect with the pathways regulated by microRNAs and how development of the knowledge of chromatin biology has enhanced our understanding of key protein-protein and protein-DNA interactions that form the HIV-1 transcriptome. Finally, we discuss the potential pharmacological approaches to target viral persistence and enhance effective transcription to purge the virus in cellular reservoirs, especially within the central nervous system, and the novel therapeutics that are currently in various stages of development to achieve a much superior prognosis for the HIV-1-infected population.
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Affiliation(s)
- Satinder Dahiya
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Michael R Nonnemacher
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Brian Wigdahl
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA
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28
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Shah PS, Schaffer DV. Antiviral RNAi: translating science towards therapeutic success. Pharm Res 2011; 28:2966-82. [PMID: 21826573 PMCID: PMC5012899 DOI: 10.1007/s11095-011-0549-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 07/25/2011] [Indexed: 01/07/2023]
Abstract
Viruses continuously evolve to contend with an ever-changing environment that involves transmission between hosts and sometimes species, immune responses, and in some cases therapeutic interventions. Given the high mutation rate of viruses relative to the timescales of host evolution and drug development, novel drug classes that are readily screened and translated to the clinic are needed. RNA interference (RNAi)-a natural mechanism for specific degradation of target RNAs that is conserved from plants to invertebrates and vertebrates-can potentially be harnessed to yield therapies with extensive specificity, ease of design, and broad application. In this review, we discuss basic mechanisms of action and therapeutic applications of RNAi, including design considerations and areas for future development in the field.
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Affiliation(s)
- Priya S. Shah
- Department of Chemical and Biolmolecular Engineering, University of California, Berkeley, California 94720 USA
| | - David V. Schaffer
- Department of Chemical and Biolmolecular Engineering, University of California, Berkeley, California 94720 USA
- Department of Bioengineering, University of California, Berkeley, California 94720 USA
- Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720 USA
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Suzuki K, Ishida T, Yamagishi M, Ahlenstiel C, Swaminathan S, Marks K, Murray D, McCartney EM, Beard MR, Alexander M, Purcell DFJ, Cooper DA, Watanabe T, Kelleher AD. Transcriptional gene silencing of HIV-1 through promoter targeted RNA is highly specific. RNA Biol 2011; 8:1035-46. [PMID: 21955498 DOI: 10.4161/rna.8.6.16264] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We have previously reported induction of transcriptional gene silencing (TGS) of HIV-1 by short hairpin RNA (shRNA) expressed in MOLT-4 cells. The shRNA (termed shPromA) targets the highly conserved tandem NF-kB binding sequences of the HIV-1 promoter. Recent articles have reported that TGS mediated by promoter-targeted siRNAs was exclusively the result of sequence non-specific off-target effects. Specifically, several mismatched siRNAs to the target promoter sequences were reported to also induce significant TGS, suggesting TGS was a consequence of off-target effects. Here, following extensive investigation, we report that shPromA induces sequence specific transcriptional silencing in HIV-1 infection in MOLT4 cells, while four shRNA variants, mismatched by 2-3 nucleotides, fail to suppress viral replication. We confirm similar levels of shRNA expression from the U6 promoter and the presence of processed/cleaved siRNAs for each construct in transduced MOLT-4 cells. HIV-1 sequence specific shPromA does not suppress HIV-2, which has an alternate NF-kB binding sequence. As a result of the unique sequence targeted, shPromA does not induce down-regulation of other NF-kB driven genes, either at the mRNA or protein level. Furthermore, we confirmed shPromA does not have sequence non-specific off-target effects through unaltered expression of CD4, CXCR4, and CCR5, which are used for viral entry. Additionally, shPromA does not alter PKR, IFN levels, and three downstream mediators of IFN-a response genes. Our data clearly shows that shPromA achieved highly specific TGS of HIV-1, demonstrating that effective TGS can be induced with minimal off-target effects.
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Affiliation(s)
- Kazuo Suzuki
- Immunovirology Laboratory, St Vincent's Centre for Applied Medical Research; Darlinghurst, NSW Australia.
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The cellular TAR RNA binding protein, TRBP, promotes HIV-1 replication primarily by inhibiting the activation of double-stranded RNA-dependent kinase PKR. J Virol 2011; 85:12614-21. [PMID: 21937648 DOI: 10.1128/jvi.05240-11] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The TAR RNA binding protein, TRBP, is a cellular double-stranded RNA (dsRNA) binding protein that can promote the replication of HIV-1 through interactions with the viral TAR element as well as with cellular proteins that affect the efficiency of translation of viral transcripts. The structured TAR element, present on all viral transcripts, can impede efficient translation either by sterically blocking access of translation initiation factors to the 5'-cap or by activating the dsRNA-dependent kinase, PKR. Several mechanisms by which TRBP can facilitate translation of viral transcripts have been proposed, including the binding and unwinding of TAR and the suppression of PKR activation. Further, TRBP has been identified as a cofactor of Dicer in the processing of microRNAs (miRNAs), and sequestration of TRBP by TAR in infected cells has been proposed as a viral countermeasure to potential host cell RNA interference-based antiviral activities. Here, we have addressed the relative importance of these various roles for TRBP in HIV-1 replication. Using Jurkat T cells, primary human CD4(+) T cells, and additional cultured cell lines, we show that depletion of TRBP has no effect on viral replication when PKR activation is otherwise blocked. Moreover, the presence of TAR-containing mRNAs does not affect the efficacy of cellular miRNA silencing pathways. These results establish that TRBP, when expressed at physiological levels, promotes HIV-1 replication mainly by suppressing the PKR-mediated antiviral response, while its contribution to HIV-1 replication through PKR-independent pathways is minimal.
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31
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Sun G, Rossi JJ. MicroRNAs and their potential involvement in HIV infection. Trends Pharmacol Sci 2011; 32:675-81. [PMID: 21862142 DOI: 10.1016/j.tips.2011.07.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 07/15/2011] [Accepted: 07/21/2011] [Indexed: 12/12/2022]
Abstract
Treatment and cure of HIV-1 infection remain one of the greatest therapeutic challenges owing to its persistent infection, which often leads to AIDS. Although it has been 28 years since the discovery of the virus, the development of an effective vaccine is still years away. Relatively newly discovered miRNAs are a family of small noncoding RNAs that can regulate gene expression primarily by binding to the 3' untranslated region of targeted transcripts. An understanding of how HIV-1 infection affects the host miRNA pathway could generate new insights into the basic mechanisms underlying HIV-1-mediated pathologies and T-lymphocyte depletion. Here, we review literature on the biogenesis of HIV-1-encoded miRNAs, cellular miRNAs that can directly target HIV-1 or essential cellular factors required for HIV-1 replication. We also discuss the feasibility of using miRNAs for HIV-1 therapy.
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Affiliation(s)
- Guihua Sun
- Irell & Manella Graduate School of Biological Science, Beckman Research Institute of the City of Hope, 1500 E. Duarte Road, Duarte, CA 91010-3000, USA
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Jouvenet N, Lainé S, Pessel-Vivares L, Mougel M. Cell biology of retroviral RNA packaging. RNA Biol 2011; 8:572-80. [PMID: 21691151 DOI: 10.4161/rna.8.4.16030] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Generation of infectious retroviral particles rely on the targeting of all structural components to the correct cellular sites at the correct time. Gag, the main structural protein, orchestrates the assembly process and the mechanisms that trigger its targeting to assembly sites are well described. Gag is also responsible for the packaging of the viral genome and the molecular details of the Gag/RNA interaction are well characterized. Until recently, much less was understood about the cell biology of retrovirus RNA packaging. However, novel biochemical and live-cell microscopic approaches have identified where in the cell the initial events of genome recognition by Gag occur. These recent developments have shed light on the role played by the viral genome during virion assembly. Other central issues of the cell biology of RNA packaging, such as how the Gag-RNA complex traffics through the cytoplasm towards assembly sites, await characterization.
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Wheatley AK, Kramski M, Alexander MR, Toe JG, Center RJ, Purcell DFJ. Co-expression of miRNA targeting the expression of PERK, but not PKR, enhances cellular immunity from an HIV-1 Env DNA vaccine. PLoS One 2011; 6:e18225. [PMID: 21464971 PMCID: PMC3064671 DOI: 10.1371/journal.pone.0018225] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 02/28/2011] [Indexed: 01/03/2023] Open
Abstract
Small non-coding micro-RNAs (miRNA) are important post-transcriptional regulators of mammalian gene expression that can be used to direct the knockdown of expression from targeted genes. We examined whether DNA vaccine vectors co-expressing miRNA with HIV-1 envelope (Env) antigens could influence the magnitude or quality of the immune responses to Env in mice. Human miR-155 and flanking regions from the non-protein encoding gene mirhg155 were introduced into an artificial intron within an expression vector for HIV-1 Env gp140. Using the miR-155-expressing intron as a scaffold, we developed novel vectors for miRNA-mediated targeting of the cellular antiviral proteins PKR and PERK, which significantly down-modulated target gene expression and led to increased Env expression in vitro. Finally, vaccinating BALB/c mice with a DNA vaccine vector delivering miRNA targeting PERK, but not PKR, was able to augment the generation of Env-specific T-cell immunity. This study provides proof-of-concept evidence that miRNA effectors incorporated into vaccine constructs can positively influence vaccine immunogenicity. Further testing of vaccine-encoded miRNA will determine if such strategies can enhance protective efficacy from vaccines against HIV-1 for eventual human use.
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Affiliation(s)
- Adam K. Wheatley
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
| | - Marit Kramski
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
| | - Marina R. Alexander
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
| | - Jesse G. Toe
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
- Division of Infection and Immunity, The Walter & Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | - Rob J. Center
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
| | - Damian F. J. Purcell
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia
- * E-mail:
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Veloso A, Warr GW, Browdy CL, Chapman RW. The transcriptomic response to viral infection of two strains of shrimp (Litopenaeus vannamei). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2011; 35:241-6. [PMID: 20955731 PMCID: PMC7103212 DOI: 10.1016/j.dci.2010.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 10/02/2010] [Indexed: 05/09/2023]
Abstract
The extent to which data-intensive studies of the transcriptome can provide insight into biological responses is not well defined, especially in the case of species (such as shrimp) where much physiological and biochemical knowledge is missing. In this study we took a transcriptomic approach to gain insight into the response to viral infection of two strains of the Pacific whiteleg shrimp (Litopenaeus vannamei) that differ in their resistance to Taura Syndrome Virus (TSV). Changes in gene expression in the hepatopancreas following infection with TSV and Yellow Head Virus (YHV) were assessed using a cDNA microarray containing 2469 putative unigenes. The null hypothesis tested was that significant differences between the transcriptomic responses to viral infection of resistant and sensitive strains would not be detected. This hypothesis was broadly rejected, with the most surprising observation being that the baseline (control, unchallenged) sensitive and resistant strains expressed distinguishable transcriptomic signatures. The resistant line was pre-disposed to lower expression of genes encoding viral (and host) proteins. Many of the genes differentiating resistant and sensitive lines are involved in protein metabolism, cellular trafficking, immune defense and stress response, although it was not possible to clearly identify candidate genes responsible for TSV resistance. In contrast to TSV challenge, YSV either failed to perturb the host transcriptome or created a "confused" response that was difficult to interpret.
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Affiliation(s)
- Artur Veloso
- Hollings Marine Laboratory, College of Charleston, Biology Department, Charleston, SC, USA
| | - Gregory W. Warr
- Hollings Marine Laboratory, Medical University of South Carolina, Department of Biochemistry and Molecular Biology, Charleston, SC, USA
| | - Craig L. Browdy
- Marine Resources Research Institute, South Carolina Department of Natural Resources, Charleston, SC, USA
| | - Robert W. Chapman
- Marine Resources Research Institute, South Carolina Department of Natural Resources, Charleston, SC, USA
- Corresponding author at: A205 Hollings Marine Laboratory, 331 Fort Johnson Road, Charleston, SC, USA. Tel.: +1 843 762 8860; fax: +1 843 762 8737.
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Abstract
Cellular restriction of HIV-1 replication has traditionally been thought of as protein mediated: APOBEC3G hypermutates HIV-1 genomic RNA, but is counteracted by Vif; Tetherin inhibits the release of budding virions but is counteracted by Vpu. In recent years, new evidence suggesting that miRNAs and other components of the miRNA pathway act as HIV-1 restriction factors has come to light, along with the identification of strategies that HIV-1 employs to surmount these host obstacles. In this article, we summarize and discuss the literature to date regarding the complex relationship between HIV-1 and miRNA-mediated inhibition.
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Affiliation(s)
- Karen Chiang
- Interdepartmental Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, TX, USA
| | - Andrew P Rice
- Interdepartmental Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, TX, USA
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Clerzius G, Gélinas JF, Gatignol A. Multiple levels of PKR inhibition during HIV-1 replication. Rev Med Virol 2010; 21:42-53. [PMID: 21294215 DOI: 10.1002/rmv.674] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Revised: 09/13/2010] [Accepted: 09/20/2010] [Indexed: 12/15/2022]
Abstract
Recent therapeutic approaches against HIV-1 include IFN in combination therapy for patients with coinfections or as an alternative strategy against the virus. These treatment options require a better understanding of the weak efficacy of the IFN-stimulated genes, such as the protein kinase RNA-activated (PKR), which results in viral progression. Activated PKR has a strong antiviral activity on HIV-1 expression and production in cell culture. However, PKR is not activated upon HIV-1 infection when the virus reaches high levels of replication, due to viral and cellular controls. PKR is activated by low levels of the HIV-1 trans-activation response (TAR) RNA element, but is inhibited by high levels of this double-stranded RNA. The viral Tat protein also counteracts PKR activation by several mechanisms. In addition, HIV-1 replicates only in cells that have a high level of the TAR RNA binding protein (TRBP), a strong inhibitor of PKR activation. Furthermore, increased levels of adenosine deaminase acting on RNA (ADAR1) are observed when HIV-1 replicates at high levels and the protein binds to PKR and inhibits its activation. Finally, the PKR activator (PACT) also binds to PKR during HIV-1 replication with no subsequent kinase activation. The combination of all the inhibiting pathways that prevent PKR phosphorylation contributes to a high HIV-1 production in permissive cells. Enhancing PKR activation by counteracting its inhibitory partners could establish an increased innate immune antiviral pathway against HIV-1 and could enhance the efficacy of the IFN treatment.
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Colin L, Van Lint C. Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies. Retrovirology 2009; 6:111. [PMID: 19961595 PMCID: PMC2797771 DOI: 10.1186/1742-4690-6-111] [Citation(s) in RCA: 173] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2009] [Accepted: 12/04/2009] [Indexed: 02/07/2023] Open
Abstract
The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway.
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Affiliation(s)
- Laurence Colin
- Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
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38
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Coiras M, López-Huertas MR, Pérez-Olmeda M, Alcamí J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat Rev Microbiol 2009; 7:798-812. [PMID: 19834480 DOI: 10.1038/nrmicro2223] [Citation(s) in RCA: 217] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
HIV-1 can infect both activated and resting, non-dividing cells, following which the viral genome can be permanently integrated into a host cell chromosome. Latent HIV-1 reservoirs are established early during primary infection and constitute a major barrier to eradication, even in the presence of highly active antiretroviral therapy. This Review analyses the molecular mechanisms that are necessary for the establishment of HIV-1 latency and their relationships with different cellular and anatomical reservoirs, and discusses the current treatment strategies for targeting viral persistence in reservoirs, their main limitations and future perspectives.
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Affiliation(s)
- Mayte Coiras
- AIDS Immunopathology Unit, National Centre of Microbiology, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
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Abstract
AIMS To address the possible use of RNA interference in diagnosis, prognosis and therapy of various diseases and explain the obstacles in RNA interference based therapy. METHODS Review of the literature. RESULTS AND DISCUSSION The MicroRNAs (miRNAs) were shown to play a role in various normal and pathological biological processes, i.e. the regulation of cell cycle and apoptosis, cell differentiation, wound healing process, immune system, etc. Furthermore, abnormal expression of miRNA was found in various diseases. Therefore, when the sample can be easily collected, miRNA expression profile can be used to detect diseases where early diagnosis is advantageous, such as in various malignancies or diseases that show myriads of symptoms such as autoimmune diseases. Further, different expression of miRNA in tumour subtypes can be used to predict the subtypes and hence the prognosis. For therapy, small (short) interfering RNAs (siRNAs) can be developed to 'switch off' up-regulated genes or miRNAs or the suppressors of down-regulated genes or miRNAs. These approaches in various animal models of diseases showed promising results and human trials for viral infections are underway. However, obstacles to the application in human might be encountered, such as degradation of the siRNAs before it can exert its function, target cell penetration and 'off target' toxic effects. Still, it is believed that modification of the RNA, development of carrier vehicles and mode and route of administration might solve these obstacles. CONCLUSION MicroRNAs profile differences between normal and pathological condition might be promising as biomarker in early diagnosis and prognosis, while siRNA showed promising result in the therapy of various diseases in animal models.
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Affiliation(s)
- J A Pawitan
- Department of Histology, Faculty of Medicine, University of Indonesia, Jakarta Pusat, Jakarta, Indonesia.
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ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. J Virol 2009; 83:10119-28. [PMID: 19605474 DOI: 10.1128/jvi.02457-08] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The interferon-induced protein kinase RNA activated (PKR) is activated after virus infection. This activation is transient during the human immunodeficiency virus type 1 (HIV-1) infection of lymphocytes, and the protein is not activated at the peak of infection. We observed that interferon-induced adenosine deaminase acting on RNA 1-p150 (ADAR1-p150) and ADAR1-p110 expression increases while the virus replicates actively. Furthermore, both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. We observed that ADAR1-p150, as previously shown for the TAR RNA binding protein (TRBP), reverses the PKR inhibition of HIV expression and production in HEK 293T cells. This activity requires the Z-DNA binding motif and the three double-stranded RNA binding domains but not the catalytic domain. In astrocytic cells, ADAR1-p150 increased HIV expression and production to an extent similar to that of TRBP. Small interfering RNAs against ADAR1-p150 moderately decreased HIV production. These results indicate that two interferon-induced proteins, ADAR1 and PKR, have antagonistic functions on HIV production. They suggest that ADAR1 and TRBP belong to a multiprotein complex that inhibits PKR during the HIV infection of lymphocytes.
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Daniels SM, Melendez-Peña CE, Scarborough RJ, Daher A, Christensen HS, El Far M, Purcell DFJ, Lainé S, Gatignol A. Characterization of the TRBP domain required for dicer interaction and function in RNA interference. BMC Mol Biol 2009; 10:38. [PMID: 19422693 PMCID: PMC2685382 DOI: 10.1186/1471-2199-10-38] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2008] [Accepted: 05/07/2009] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Dicer, Ago2 and TRBP are the minimum components of the human RNA-induced silencing complex (RISC). While Dicer and Ago2 are RNases, TRBP is the double-stranded RNA binding protein (dsRBP) that loads small interfering RNA into the RISC. TRBP binds directly to Dicer through its C-terminal domain. RESULTS We show that the TRBP binding site in Dicer is a 165 amino acid (aa) region located between the ATPase and the helicase domains. The binding site in TRBP is a 69 aa domain, called C4, located at the C-terminal end of TRBP. The TRBP1 and TRBP2 isoforms, but not TRBPs lacking the C4 site (TRBPsDeltaC4), co-immunoprecipitated with Dicer. The C4 domain is therefore necessary to bind Dicer, irrespective of the presence of RNA. Immunofluorescence shows that while full-length TRBPs colocalize with Dicer, TRBPsDeltaC4 do not. tarbp2-/- cells, which do not express TRBP, do not support RNA interference (RNAi) mediated by short hairpin or micro RNAs against EGFP. Both TRBPs, but not TRBPsDeltaC4, were able to rescue RNAi function. In human cells with low RNAi activity, addition of TRBP1 or 2, but not TRBPsDeltaC4, rescued RNAi function. CONCLUSION The mapping of the interaction sites between TRBP and Dicer show unique domains that are required for their binding. Since TRBPsDeltaC4 do not interact or colocalize with Dicer, we suggest that TRBP and Dicer, both dsRBPs, do not interact through bound dsRNA. TRBPs, but not TRBPsDeltaC4, rescue RNAi activity in RNAi-compromised cells, indicating that the binding of Dicer to TRBP is critical for RNAi function.
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Affiliation(s)
- Sylvanne M Daniels
- Virus-Cell Interactions Laboratory, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
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Keating CP, Hill MK, Hawkes DJ, Smyth RP, Isel C, Le SY, Palmenberg AC, Marshall JA, Marquet R, Nabel GJ, Mak J. The A-rich RNA sequences of HIV-1 pol are important for the synthesis of viral cDNA. Nucleic Acids Res 2008; 37:945-56. [PMID: 19106143 PMCID: PMC2647285 DOI: 10.1093/nar/gkn1015] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The bias of A-rich codons in HIV-1 pol is thought to be a record of hypermutations in viral genomes that lack biological functions. Bioinformatic analysis predicted that A-rich sequences are generally associated with minimal local RNA structures. Using codon modifications to reduce the amount of A-rich sequences within HIV-1 genomes, we have reduced the flexibility of RNA sequences in pol to analyze the functional significance of these A-rich 'structurally poor' RNA elements in HIV-1 pol. Our data showed that codon modification of HIV-1 sequences led to a suppression of virus infectivity by 5-100-fold, and this defect does not correlate with, viral entry, viral protein expression levels, viral protein profiles or virion packaging of genomic RNA. Codon modification of HIV-1 pol correlated with an enhanced dimer stability of the viral RNA genome, which was associated with a reduction of viral cDNA synthesis both during HIV-1 infection and in a cell free reverse transcription assay. Our data provided direct evidence that the HIV-1 A-rich pol sequence is not merely an evolutionary artifact of enzyme-induced hypermutations, and that HIV-1 has adapted to rely on A-rich RNA sequences to support the synthesis of viral cDNA during reverse transcription, highlighting the utility of using 'structurally poor' RNA domains in regulating biological process.
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Affiliation(s)
- Cameron P Keating
- Centre for Virology, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia
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TRBP control of PACT-induced phosphorylation of protein kinase R is reversed by stress. Mol Cell Biol 2008; 29:254-65. [PMID: 18936160 DOI: 10.1128/mcb.01030-08] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The TAR RNA binding Protein, TRBP, inhibits the activity of the interferon-induced protein kinase R (PKR), whereas the PKR activator, PACT, activates its function. TRBP and PACT also bind to each other through their double-stranded RNA binding domains (dsRBDs) and their Medipal domains, which may influence their activity on PKR. In a human immunodeficiency virus (HIV) long terminal repeat-luciferase assay, PACT unexpectedly reversed PKR-mediated inhibition of gene expression. In a translation inhibition assay in HeLa cells, PACT lacking the 13 C-terminal amino acids (PACTDelta13), but not full-length PACT, activated PKR and enhanced interferon-mediated repression. In contrast, in the astrocytic U251MG cells that express low TRBP levels, both proteins activate PKR, but PACTDelta13 is stronger. Immunoprecipitation assays and yeast two-hybrid assays show that TRBP and PACTDelta13 interact very weakly due to a loss of binding in the Medipal domain. PACT-induced PKR phosphorylation was restored in Tarbp2(-/-) murine tail fibroblasts and in HEK293T or HeLa cells when TRBP expression was reduced by RNA interference. In HEK293T and HeLa cells, arsenite, peroxide, and serum starvation-mediated stresses dissociated the TRBP-PACT interaction and increased PACT-induced PKR activation, demonstrating the relevance of this control in a physiological context. Our results demonstrate that in cells, TRBP controls PACT activation of PKR, an activity that is reversed by stress.
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Abstract
In this review, a quick presentation of what interfering RNA (iRNA) are—small RNA able to exert an inhibition on gene expression at a posttranscriptional level, based on sequence homology between the iRNA and the mRNA—will be given. The many faces of the interrelations between iRNA and viruses, particularly HIV, will be reviewed. Four kinds of interactions have been described: i) iRNA of viral origin blocking viral RNA, ii) iRNA of viral origin downregulating cellular mRNA, iii) iRNA of cellular origin (microRNA) targeting viral RNA, and iv) microRNA downregulating cellular mRNA encoding cell proteins used by the virus for its replication. Next, HIV strategies to manipulate these interrelations will be considered: suppression of iRNA biosynthesis by Tat, trapping by the HIV TAR sequence of a cell component, TRBP, necessary for iRNA production and action, and induction by the virus of some microRNA together with suppression of others. Then, we will discuss the putative effects of these mutual influences on viral replication as well as on viral latency, immune response, and viral cytopathogenicity. Finally, the potential consequences on the human infection of genetic polymorphisms in microRNA genes and the therapeutic potential of iRNA will be presented.
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Affiliation(s)
- Pierre Corbeau
- Laboratoire d'Immunologie, Hôpital Carémeau, Nîmes and Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
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45
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van Rij RP. Virus meets RNAi. Symposium on antiviral applications of RNA interference. EMBO Rep 2008; 9:725-9. [PMID: 18636088 DOI: 10.1038/embor.2008.133] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2008] [Accepted: 06/17/2008] [Indexed: 11/09/2022] Open
Affiliation(s)
- Ronald P van Rij
- Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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Van Duyne R, Cardenas J, Easley R, Wu W, Kehn-Hall K, Klase Z, Mendez S, Zeng C, Chen H, Saifuddin M, Kashanchi F. Effect of transcription peptide inhibitors on HIV-1 replication. Virology 2008; 376:308-22. [PMID: 18455747 DOI: 10.1016/j.virol.2008.02.036] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2007] [Revised: 12/21/2007] [Accepted: 02/27/2008] [Indexed: 11/17/2022]
Abstract
HIV-1 manipulates cellular machineries such as cyclin dependent kinases (cdks) and their cyclin elements, to stimulate virus production and maintain latent infection. Specifically, the HIV-1 viral protein Tat increases viral transcription by binding to the TAR promoter element. This binding event is mediated by the phosphorylation of Pol II by complexes such as cdk9/Cyclin T and cdk2/Cyclin E. Recent studies have shown that a Tat 41/44 peptide derivative prevents the loading of cdk2 onto the HIV-1 promoter, inhibiting gene expression and replication. Here we show that Tat peptide analogs computationally designed to dock at the cyclin binding site of cdk2 have the ability to bind to cdk2 and inhibit the association of cdk2 with the HIV promoter. Specifically, the peptide LAALS dissociated the complex and decreased kinase activity in vitro. We also describe our novel small animal model which utilizes humanized Rag2(-/-)gamma(c)(-/-) mice. This small peptide inhibitor induces a decrease in HIV-1 viral transcription in vitro and minimizes viral loads in vivo.
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Affiliation(s)
- Rachel Van Duyne
- The George Washington University Medical Center, Department of Microbiology, Immunology, and Tropical Medicine, Washington, DC 20037, USA.
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47
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Scherer L, Weinberg MS, Rossi JJ. RNA Based Therapies for Treatment of HIV Infection. THERAPEUTIC OLIGONUCLEOTIDES 2008. [DOI: 10.1039/9781847558275-00316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Lisa Scherer
- Division of Molecular Biology City of Hope Beckman Research Institute Duarte CA
| | - Marc S. Weinberg
- Department of Molecular Medicine and Hematology University of the Witwatersrand Medical School Wits South Africa
| | - John J. Rossi
- Division of Molecular Biology City of Hope Beckman Research Institute Duarte CA
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Abstract
Life-prolonging antiretroviral therapy remarkably reduces viral load, but it does not eradicate the virus. An important obstacle preventing virus clearance is the presence of latent virion reservoirs in the host. However, new promising antiviral approaches are emerging, and a number of host cell factors involved in the disease progression and control of HIV-1 replication have been recently discovered. For instance, the RNA interference (RNAi) mechanism, besides many functions conserved throughout evolution, works as a defence mechanism against noxious transcripts which may provide a new tool to block viral replication. The recent definition of basic RNAi mechanisms, as well as the discovery of micro RNAs (microRNAs) encoded by the host cell genome and by HIV-1, also suggest that RNAi may be involved in the control of HIV replication.
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Affiliation(s)
- Luis Isamu Barros Kanzaki
- Laboratory of Molecular Pharmacology, Faculty of Health Science, University of Brasília, Brasília, Brazil
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49
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Dieckhoff B, Petersen B, Kues WA, Kurth R, Niemann H, Denner J. Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs. Xenotransplantation 2008; 15:36-45. [DOI: 10.1111/j.1399-3089.2008.00442.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Scherer L, Rossi JJ, Weinberg MS. Progress and prospects: RNA-based therapies for treatment of HIV infection. Gene Ther 2007; 14:1057-64. [PMID: 17607313 DOI: 10.1038/sj.gt.3302977] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The current treatment regimen for HIV-infected individuals combines two or more drugs targeting different viral proteins such as RT and gag. Resistance to conventional drugs can develop quickly, and typically persists. The prospect of longer, continuous antiretroviral therapy brings with it the need for new antiretroviral drugs and approaches. In this context, gene therapies have the potential to prolong life and quality of life as an additional therapeutic class and may serve as an adjuvant to traditional treatments. This review focuses on RNA-based hematopoietic cell gene therapy for treatment of HIV infection. Recent advances in our understanding of RNA interference (RNAi) make this an especially attractive candidate for anti-HIV gene therapy although ribozyme and RNA decoy/aptamer approaches can be combined with RNAi to make a combinatorial therapy akin to highly active anti-retroviral therapy.
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Affiliation(s)
- L Scherer
- Division of Molecular Biology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
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