Hepatitis B Virus Reverse Transcriptase: Diverse Functions As Classical and Emerging Targets for Antiviral Intervention

Overview

Journal Emerg Microbes Infect

Specialty Infectious Diseases

Date 2015 Jun 4

PMID 26038488

Citations 51

Authors

Scott A Jones

Jianming Hu

Affiliations

Soon will be listed here.

Abstract

Hepatitis B virus (HBV) infection remains a global health problem with over 350 million chronically infected, causing an increased risk of cirrhosis and hepatocellular carcinoma. Current antiviral chemotherapy for HBV infection include five nucleos(t)ide analog reverse transcriptase inhibitors (NRTIs) that all target one enzymatic activity, DNA strand elongation, of the HBV polymerase (HP), a specialized reverse transcriptase (RT). NRTIs are not curative and long-term treatment is associated with toxicity and the emergence of drug resistant viral mutations, which can also result in vaccine escape. Recent studies on the multiple functions of HP have provided important mechanistic insights into its diverse roles during different stages of viral replication, including interactions with viral pregenomic RNA, RNA packaging into nucleocapsids, protein priming, minus- and plus-strand viral DNA synthesis, RNase H-mediated degradation of viral RNA, as well as critical host interactions that regulate the multiple HP functions. These diverse functions provide ample opportunities to develop novel HP-targeted antiviral treatments that should contribute to curing chronic HBV infection.

Citing Articles

Genotyping Hepatitis B virus by Next-Generation Sequencing: Detection of Mixed Infections and Analysis of Sequence Conservation.

Dopico E, Vila M, Tabernero D, Gregori J, Rando-Segura A, Pacin-Ruiz B Int J Mol Sci. 2024; 25(10).

PMID: 38791519 PMC: 11122360. DOI: 10.3390/ijms25105481.

HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma.

Jia Y, Zhao J, Wang C, Meng J, Zhao L, Yang H J Transl Med. 2024; 22(1):272.

PMID: 38475878 PMC: 10936085. DOI: 10.1186/s12967-024-05069-y.

Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target.

Olenginski L, Attionu S, Henninger E, LeBlanc R, Longhini A, Dayie T Viruses. 2023; 15(9).

PMID: 37766319 PMC: 10534774. DOI: 10.3390/v15091913.

RNA binding protein TIAR modulates HBV replication by tipping the balance of pgRNA translation.

Zhang T, Zheng H, Lu D, Guan G, Li D, Zhang J Signal Transduct Target Ther. 2023; 8(1):346.

PMID: 37699883 PMC: 10497612. DOI: 10.1038/s41392-023-01573-7.

Pre- and Post-Transcriptional Control of HBV Gene Expression: The Road Traveled towards the New Paradigm of HBx, Its Isoforms, and Their Diverse Functions.

Villanueva R, Loyola A Biomedicines. 2023; 11(6).

PMID: 37371770 PMC: 10296101. DOI: 10.3390/biomedicines11061674.

References

Wang Y, Wen Y, Nassal M . Carbonyl J acid derivatives block protein priming of hepadnaviral P protein and DNA-dependent DNA synthesis activity of hepadnaviral nucleocapsids. J Virol. 2012; 86(18):10079-92. PMC: 3446557. DOI: 10.1128/JVI.00816-12. View

Shin Y, Ko C, Ryu W . Hydrophobic residues of terminal protein domain of hepatitis B virus polymerase contribute to distinct steps in viral genome replication. FEBS Lett. 2011; 585(24):3964-8. DOI: 10.1016/j.febslet.2011.11.003. View

Blum H, Galun E, Liang T, von Weizsacker F, Wands J . Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication. J Virol. 1991; 65(4):1836-42. PMC: 239993. DOI: 10.1128/JVI.65.4.1836-1842.1991. View

Ariumi Y, Kuroki M, Abe K, Dansako H, Ikeda M, Wakita T . DDX3 DEAD-box RNA helicase is required for hepatitis C virus RNA replication. J Virol. 2007; 81(24):13922-6. PMC: 2168844. DOI: 10.1128/JVI.01517-07. View

Owsianka A, Patel A . Hepatitis C virus core protein interacts with a human DEAD box protein DDX3. Virology. 1999; 257(2):330-40. DOI: 10.1006/viro.1999.9659. View

Das K, Xiong X, Yang H, Westland C, Gibbs C, Sarafianos S . Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). J Virol. 2001; 75(10):4771-9. PMC: 114232. DOI: 10.1128/JVI.75.10.4771-4779.2001. View

Staschke K, Colacino J . Priming of duck hepatitis B virus reverse transcription in vitro: premature termination of primer DNA induced by the 5'-triphosphate of fialuridine. J Virol. 1994; 68(12):8265-9. PMC: 237293. DOI: 10.1128/JVI.68.12.8265-8269.1994. View

Seeger C, Leber E, Wiens L, Hu J . Mutagenesis of a hepatitis B virus reverse transcriptase yields temperature-sensitive virus. Virology. 1996; 222(2):430-9. DOI: 10.1006/viro.1996.0440. View

Huang H, Chopra R, Verdine G, Harrison S . Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science. 1998; 282(5394):1669-75. DOI: 10.1126/science.282.5394.1669. View

10.

Foster G, Ackrill A, Goldin R, Kerr I, Thomas H, Stark G . Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA. Proc Natl Acad Sci U S A. 1991; 88(7):2888-92. PMC: 51345. DOI: 10.1073/pnas.88.7.2888. View

11.

Nowotny M, Gaidamakov S, Crouch R, Yang W . Crystal structures of RNase H bound to an RNA/DNA hybrid: substrate specificity and metal-dependent catalysis. Cell. 2005; 121(7):1005-16. DOI: 10.1016/j.cell.2005.04.024. View

12.

Weber M, Bronsema V, Bartos H, Bosserhoff A, Bartenschlager R, Schaller H . Hepadnavirus P protein utilizes a tyrosine residue in the TP domain to prime reverse transcription. J Virol. 1994; 68(5):2994-9. PMC: 236789. DOI: 10.1128/JVI.68.5.2994-2999.1994. View

13.

Boregowda R, Adams C, Hu J . TP-RT domain interactions of duck hepatitis B virus reverse transcriptase in cis and in trans during protein-primed initiation of DNA synthesis in vitro. J Virol. 2012; 86(12):6522-36. PMC: 3393569. DOI: 10.1128/JVI.00086-12. View

14.

Kim S, Lee J, Ryu W . Four conserved cysteine residues of the hepatitis B virus polymerase are critical for RNA pregenome encapsidation. J Virol. 2009; 83(16):8032-40. PMC: 2715788. DOI: 10.1128/JVI.00332-09. View

15.

Hu J, Boyer M . Hepatitis B virus reverse transcriptase and epsilon RNA sequences required for specific interaction in vitro. J Virol. 2006; 80(5):2141-50. PMC: 1395402. DOI: 10.1128/JVI.80.5.2141-2150.2006. View

16.

Hsu C, Yeh C, Chang M, Liaw Y . Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HBsAg seroclearance. Gastroenterology. 2007; 132(2):543-50. DOI: 10.1053/j.gastro.2006.12.001. View

17.

Hu J, Seeger C . Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase. Proc Natl Acad Sci U S A. 1996; 93(3):1060-4. PMC: 40030. DOI: 10.1073/pnas.93.3.1060. View

18.

Radziwill G, Tucker W, Schaller H . Mutational analysis of the hepatitis B virus P gene product: domain structure and RNase H activity. J Virol. 1990; 64(2):613-20. PMC: 249151. DOI: 10.1128/JVI.64.2.613-620.1990. View

19.

Stahl M, Beck J, Nassal M . Chaperones activate hepadnavirus reverse transcriptase by transiently exposing a C-proximal region in the terminal protein domain that contributes to epsilon RNA binding. J Virol. 2007; 81(24):13354-64. PMC: 2168843. DOI: 10.1128/JVI.01196-07. View

20.

Lanford R, Kim Y, Lee H, Notvall L, Beames B . Mapping of the hepatitis B virus reverse transcriptase TP and RT domains by transcomplementation for nucleotide priming and by protein-protein interaction. J Virol. 1999; 73(3):1885-93. PMC: 104429. DOI: 10.1128/JVI.73.3.1885-1893.1999. View