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Yang G, Wan P, Zhang Y, Tan Q, Qudus MS, Yue Z, Luo W, Zhang W, Ouyang J, Li Y, Wu J. Innate Immunity, Inflammation, and Intervention in HBV Infection. Viruses 2022; 14:2275. [PMID: 36298831 PMCID: PMC9609328 DOI: 10.3390/v14102275] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/12/2022] [Accepted: 10/15/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still one of the most dangerous viral illnesses. HBV infects around 257 million individuals worldwide. Hepatitis B in many individuals ultimately develops hepatocellular carcinoma (HCC), which is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide. The innate immunity acts as the first line of defense against HBV infection through activating antiviral genes. Along with the immune responses, pro-inflammatory cytokines are triggered to enhance the antiviral responses, but this may result in acute or chronic liver inflammation, especially when the clearance of virus is unsuccessful. To a degree, the host innate immune and inflammatory responses dominate the HBV infection and liver pathogenesis. Thus, it is crucial to figure out the signaling pathways involved in the activation of antiviral factors and inflammatory cytokines. Here, we review the interplay between HBV and the signal pathways that mediates innate immune responses and inflammation. In addition, we summarize current therapeutic strategies for HBV infection via modulating innate immunity or inflammation. Characterizing the mechanisms that underlie these HBV-host interplays might provide new approaches for the cure of chronic HBV infection.
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Affiliation(s)
- Ge Yang
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Pin Wan
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Yaru Zhang
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
| | - Qiaoru Tan
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Muhammad Suhaib Qudus
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Zhaoyang Yue
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Wei Luo
- Clinical Research Institute, The First People’s Hospital, Foshan 528000, China
| | - Wen Zhang
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Jianhua Ouyang
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Yongkui Li
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Jianguo Wu
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
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Chang HL, Wen WH, Lee CN, Chiu YE, Liu CJ, Chang MH, Lin LH, Chen HL. Kinetics of hepatitis B surface antigen in pregnant women with and without tenofovir disoproxil fumarate. J Viral Hepat 2022; 29:107-114. [PMID: 34724288 DOI: 10.1111/jvh.13628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 09/06/2021] [Accepted: 10/24/2021] [Indexed: 12/09/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent mother-to-infant transmission in highly viremic HBV-infected women. Data on hepatitis B surface antigen (HBsAg) levels in pregnant women are lacking. We aimed to investigate prepartum and postpartum HBsAg kinetics and its correlation with HBV DNA in pregnant women. HBV-infected mothers with HBV DNA ≥7.5 log10 IU/ml were tested for HBsAg and HBV DNA from baseline to 6 months postpartum. Of the 186 pregnant women with comparable baseline HBsAg and HBV DNA, 101 received TDF from the third trimester until 1 month postpartum. At delivery, TDF group had mildly lower HBsAg (4.32 ± 0.47 vs. 4.54 ± 0.35 log10 IU/ml, p = .0004) and markedly lower HBV DNA (4.26 ± 0.97 vs. 8.11 ± 0.70 log10 IU/ml, p < .0001) than the control group. In the TDF group, mean reduction of HBsAg and HBV DNA from baseline to delivery were 0.22 ± 0.38 and 3.96 ± 0.93 log10 IU/ml. HBsAg reduction had a positive correlation (r = .309; p = .0017) with HBV DNA reduction, and was predictive of HBV DNA reduction ≥3 log10 IU/ml (area under the receiver operating characteristic curve, 0.67; 95% confidence interval, 0.50-0.82). At 6 months postpartum, TDF and control group had comparable HBsAg and HBV DNA. In conclusion, HBsAg decreased slightly at delivery in pregnant women receiving TDF. For monitoring the effect of antiviral therapy during pregnancy, HBV DNA is a better marker than HBsAg. Our data provided valuable information regarding monitoring HBV-infected pregnant women using antiviral therapy.
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Affiliation(s)
- Huai-Lung Chang
- School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Hsin Wen
- Department of Pediatrics, Cardinal Tien Hospital, New Taipei City, Taiwan.,School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Chien-Nan Lee
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yu-En Chiu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Lung-Huang Lin
- Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department and Graduate Institute of Medical Education and Bioethics, National Taiwan University College of Medicine, Taipei, Taiwan
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Zeng Y, Li Z, Shang J, Kang Y. Efficient delivery of HBV NLS siRNAs into HepG2.2.15 cells for HBV inhibition through novel recombinant preS1‑tP proteins. Int J Mol Med 2018; 42:1181-1189. [PMID: 29786106 DOI: 10.3892/ijmm.2018.3681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/08/2018] [Indexed: 11/05/2022] Open
Abstract
Hepatitis B virus (HBV) infection and related liver complications remain severe public health problems worldwide. Previous investigations have shown that small interfering (si)RNAs can offer an effective strategy for the treatment of chronic hepatitis B. The present study aimed to develop a novel siRNA‑delivering system of therapeutic HBV nuclear localization sequence (NLS) siRNAs using the recombinant preS1‑truncated protamine (tP) proteins. The preS1 region of the LHB was used in place of scFv to construct the recombinant preS1‑tP proteins, which were applied to deliver siRNAs targeting the HBV NLS to inhibit HBV replication and infection in HepG2.2.15 cells overexpressing sodium taurocholate cotransporting polypeptide (NTCP). The results revealed that HepG2.2.15 cells with stable NTCP expression (HepG2.2.15‑NTCP cells) transfected with the recombinant lentivirus showed increased expression of NTCP genes. The HBV NLS siRNAs significantly suppressed HBV mRNA content and levels of HBsAg and HBeAg in the HepG2.2.15‑NTCP cells. Recombinant preS1‑tP proteins tagged with His and glutathione S‑transferase were found to enter into HepG2.2.15‑NTCP cells and bind with DNA. The HBV NLS siRNAs were delivered into HepG2.2.15‑NTCP cells by recombinant preS1‑tP proteins, which resulted in decreased expression of HBV mRNA, HBsAg and HBeAg, HBV DNA and covalently closed circular DNA in the HepG2.2.15‑NTCP cells. Therefore, the recombinant preS1‑tP proteins successfully delivered NLS siRNAs into HepG2.2.15 cells and repressed HBV infection and replication.
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Affiliation(s)
- Yanli Zeng
- Department of Infectious Diseases, Zhengzhou University People's Hospital, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Zixi Li
- Tongji Medical College of Huazhong University of Science and Technology Affiliated Hospital of Traditional Chinese and Western Medicine, Wuhan, Hubei 430030, P.R. China
| | - Jia Shang
- Department of Infectious Diseases, Zhengzhou University People's Hospital, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Yi Kang
- Department of Infectious Diseases, Zhengzhou University People's Hospital, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
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Phyo WW, Soh AYS, Lim SG, Lee GH. Search for a cure for chronic hepatitis B infection: How close are we? World J Hepatol 2015; 7:1272-1281. [PMID: 26019743 PMCID: PMC4438502 DOI: 10.4254/wjh.v7.i9.1272] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/19/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) remains a significant unmet medical need, with 240 million chronically infected persons worldwide. It can be controlled effectively with either nucleoside/nucleotide-based or interferon-based therapies. However, most patients receiving these therapies will relapse after treatment withdrawal. During recent years, the advances in molecular biology and immunology have enabled a better understanding of the viral-host interaction and inspired new treatment approaches to achieve either elimination of the virus from the liver or durable immune control of the infection. This review aims to provide a brief overview on the potential new therapies that may overcome the challenge of persistent CHB infection in the near future.
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Association between HBV Pre-S mutations and the intracellular HBV DNAs in HBsAg-positive hepatocellular carcinoma in China. Clin Exp Med 2014; 15:483-91. [PMID: 25501679 DOI: 10.1007/s10238-014-0321-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023]
Abstract
This study aimed to investigate the association between HBV mutations and intrahepatic HBV status and to determine the clinical features and the contribution of HBV mutations to postoperative prognosis for hepatocellular carcinoma (HCC) patients with HBsAg (+) in China. Using TaqMan fluorescent real-time PCR, HBV covalently closed circular DNA (cccDNA) and total DNA (tDNA) were both quantified in 106 pairs of tumor tissues (TT) and adjacent non-tumor tissues (ANTT) obtained from HCC patients who received no antiviral treatment before surgical treatment. The prevalence of 19 hot spot mutations was evaluated by Sanger sequencing. HBV cccDNA and tDNA were lower in TT than in ANTT. The loads of cccDNA and tDNA in ANTT were associated with serum HBV DNA and HBeAg. Three Pre-S mutants (A2962G and C2964A in Pre-S1 and C105T in Pre-S2) were associated with higher tumor cccDNA levels (P < 0.05), and A2962G/C2964A mutants were associated with higher AFP levels. This would assist to disclose the virological features, to implement a more clinically personalized therapy and to improve the prognosis of HBV-related HCC patients.
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Tang B, Wang YM, Liu J, Zhang R. Detection of hepatitis B virus cccDNA with modified polymerase chain reaction. Shijie Huaren Xiaohua Zazhi 2005; 13:2188-2192. [DOI: 10.11569/wcjd.v13.i18.2188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a simple and fast hepatitis B virus covalently closed circular DNA(cccDNA) detecting method based on polymerase chain reaction(PCR) with satisfactory sensitivity and specificity.
METHODS: The cccDNA and the relaxed circular DNA (rcDNA) were extracted from HepG2.2.15 cells and supernatant, respectively, and then purified. Two pairs of specific PCR primes were designed to cover the single strand area of rcDNA. And two pairs of non-specific PCR primes were designed to cover the double strand area of rcDNA. Before and after digested by single-strand-specific mung bean nuclease(MBN), cccDNA and rcDNA samples were amplified by specific primes and non-specific primes. Whether the digested cccDNA can be amplified by specific primes, without amplifying the digested rcDNA, was observed. The PCR parameters such as substrate amount and circulation times were changed during amplification. The HBV genome plasmid was used as control; and the HBV samples from patient with hepatitis B was used for practical test.
RESULTS: Different amounts of rcDNA template were amplified by specific and non-specific primes. More than 104 and 102 rcDNA template molecules were amplified by two pairs of specific and non-specific primes, respectively. The specific primes could not discriminate between rcDNA and cccDNA when the template molecules were overabundant. Before and after the digestion by MBN, different amounts of cccDNA were amplified by specific and non-specific primes; and after the digestion, rcDNA templates were amplified by non-specific primes, but not by specific primes. With this strategy, we found the virus samples from the serum of the patient with chronic hepatitis B contained mainly rcDNA and a small quantity of cccDNA, while the samples from hepatocytes contained mainly cccDNA.
CONCLUSION: The combination of MBN selective digestion and specific PCR amplification of the cccDNA is a simple, fast, sensitive and specific method for the detection of HBV cccDNA.
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