Naturally Occurring Missense Mutation in the Polymerase Gene Terminating Hepatitis B Virus Replication

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 1991 Apr 1

PMID 2002544

Citations 36

Authors

H E Blum

E Galun

T J Liang

F von Weizsacker

J R Wands

Affiliations

Soon will be listed here.

Abstract

A hepatitis B virus (HBV) genome was cloned from human liver. Numerous mutations in all viral genes define this HBV DNA as a mutant, divergent from all known HBV DNA sequences. Functional analyses of this mutant demonstrated a defect blocking viral DNA synthesis. The genetic basis of this defect was identified as a single missense mutation in the 5' region of the viral polymerase gene, resulting in the inability to package pregenomic RNA into core particles. The replication defect could be trans-complemented by a full-length wild-type, but not by a full-length mutant or 3'-truncated wild-type, polymerase gene construct. Our findings indicate a critical role of the 5' polymerase gene region in the life cycle of the virus and suggest that introducing missense mutations in this region can be a strategy to terminate viral replication in vivo.

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References

LAVINE J, Hirsch R, Ganem D . A system for studying the selective encapsidation of hepadnavirus RNA. J Virol. 1989; 63(10):4257-63. PMC: 251040. DOI: 10.1128/JVI.63.10.4257-4263.1989. View

Tiollais P, Pourcel C, Dejean A . The hepatitis B virus. Nature. 1985; 317(6037):489-95. DOI: 10.1038/317489a0. View

Horwich A, Furtak K, Pugh J, Summers J . Synthesis of hepadnavirus particles that contain replication-defective duck hepatitis B virus genomes in cultured HuH7 cells. J Virol. 1990; 64(2):642-50. PMC: 249155. DOI: 10.1128/JVI.64.2.642-650.1990. View

Feitelson M, Millman I, Halbherr T, Simmons H, Blumberg B . A newly identified hepatitis B type virus in tree squirrels. Proc Natl Acad Sci U S A. 1986; 83(7):2233-7. PMC: 323266. DOI: 10.1073/pnas.83.7.2233. View

Seeger C, Ganem D, Varmus H . Biochemical and genetic evidence for the hepatitis B virus replication strategy. Science. 1986; 232(4749):477-84. DOI: 10.1126/science.3961490. View

Miller R, ROBINSON W . Common evolutionary origin of hepatitis B virus and retroviruses. Proc Natl Acad Sci U S A. 1986; 83(8):2531-5. PMC: 323332. DOI: 10.1073/pnas.83.8.2531. View

Enders G, Ganem D, Varmus H . 5'-terminal sequences influence the segregation of ground squirrel hepatitis virus RNAs into polyribosomes and viral core particles. J Virol. 1987; 61(1):35-41. PMC: 255195. DOI: 10.1128/JVI.61.1.35-41.1987. View

Will H, REISER W, Weimer T, Pfaff E, Buscher M, Sprengel R . Replication strategy of human hepatitis B virus. J Virol. 1987; 61(3):904-11. PMC: 254036. DOI: 10.1128/JVI.61.3.904-911.1987. View

Ganem D, Varmus H . The molecular biology of the hepatitis B viruses. Annu Rev Biochem. 1987; 56:651-93. DOI: 10.1146/annurev.bi.56.070187.003251. View

10.

Mierendorf R, PFEFFER D . Direct sequencing of denatured plasmid DNA. Methods Enzymol. 1987; 152:556-62. DOI: 10.1016/0076-6879(87)52061-4. View

11.

Chen C, Okayama H . High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987; 7(8):2745-52. PMC: 367891. DOI: 10.1128/mcb.7.8.2745-2752.1987. View

12.

Okamoto H, Tsuda F, Mayumi M . Defective mutants of hepatitis B virus in the circulation of symptom-free carriers. Jpn J Exp Med. 1987; 57(4):217-21. View

13.

Okamoto H, Imai M, Kametani M, Nakamura T, Mayumi M . Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission. Jpn J Exp Med. 1987; 57(4):231-6. View

14.

Saiki R, Gelfand D, Stoffel S, Scharf S, Higuchi R, Horn G . Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988; 239(4839):487-91. DOI: 10.1126/science.2448875. View

15.

Sprengel R, Kaleta E, Will H . Isolation and characterization of a hepatitis B virus endemic in herons. J Virol. 1988; 62(10):3832-9. PMC: 253529. DOI: 10.1128/JVI.62.10.3832-3839.1988. View

16.

Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo R, Imai M, Miyakawa Y . Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988; 69 ( Pt 10):2575-83. DOI: 10.1099/0022-1317-69-10-2575. View

17.

Bosch V, Bartenschlager R, Radziwill G, Schaller H . The duck hepatitis B virus P-gene codes for protein strongly associated with the 5'-end of the viral DNA minus strand. Virology. 1988; 166(2):475-85. DOI: 10.1016/0042-6822(88)90518-1. View

18.

Blum H, Offensperger W, Walter E, Offensperger S, Gerok W . Latent hepatitis B virus infection with full-length viral genome in a patient serologically immune to hepatitis B virus infection. Liver. 1988; 8(5):307-16. DOI: 10.1111/j.1600-0676.1988.tb01009.x. View

19.

Schlicht H, Radziwill G, Schaller H . Synthesis and encapsidation of duck hepatitis B virus reverse transcriptase do not require formation of core-polymerase fusion proteins. Cell. 1989; 56(1):85-92. DOI: 10.1016/0092-8674(89)90986-0. View

20.

Su T, Lui W, Lin L, Han S, Peng F . Analysis of hepatitis B virus transcripts in infected human livers. Hepatology. 1989; 9(2):180-5. DOI: 10.1002/hep.1840090203. View