PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
 
J Virol. 1990 March; 64(3): 1298–1303.
PMCID: PMC249247

Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen.

Abstract

The C gene of hepatitis B virus (HBV) codes for a nucleocapsid protein made of 183 amino acid residues and is preceded in phase by the precore (pre-C) region, encoding 29 residues. The pre-C-region product is required for the synthesis and secretion of hepatitis B e antigen (HBeAg), which is made of the C-terminal 10 amino acid residues of the pre-C-region product and the N-terminal 149 residues of the C-gene product. HBV mutants with pre-C-region defects prevailed in the circulation of three asymptomatic carriers as they seroconverted from HBeAg to the corresponding antibody (anti-HBe), and these mutants finally replaced nondefective HBV. HBV DNA clones were propagated from sera of an additional 15 carriers with anti-HBe and sequenced for the pre-C region. Essentially all HBV DNA clones (56 of 57 [98%]) revealed mutations that prohibited the translation of a functional pre-C-region product. A point mutation from G to A at nucleotide 83, converting Trp-28 (TGG) to a stop codon (TAG), was by far the commonest and was observed in HBV DNA clones from 16 (89%) of 18 carriers seropositive for anti-HBe. In addition, there were point mutations involving ATG codon to abort the translation initiation of the pre-C region, as well as deletion and insertion to induce frameshifts. Such mutations leading to pre-C-region defects were rarely observed in persistently infected individuals positive for HBeAg or in patients with type B acute hepatitis after they had seroconverted to anti-HBe. These results would indicate a selection of pre-C-defective mutants in persistently infected hosts, along with seroconversion to anti-HBe, by immune elimination of hepatocytes harboring nondefective HBV with the expression of HBeAg.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Alter HJ, Seeff LB, Kaplan PM, McAuliffe VJ, Wright EC, Gerin JL, Purcell RH, Holland PV, Zimmerman HJ. Type B hepatitis: the infectivity of blood positive for e antigen and DNA polymerase after accidental needlestick exposure. N Engl J Med. 1976 Oct 21;295(17):909–913. [PubMed]
  • Bonino F, Rosina F, Rizzetto M, Rizzi R, Chiaberge E, Tardanico R, Callea F, Verme G. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology. 1986 May;90(5 Pt 1):1268–1273. [PubMed]
  • Bruss V, Gerlich WH. Formation of transmembraneous hepatitis B e-antigen by cotranslational in vitro processing of the viral precore protein. Virology. 1988 Apr;163(2):268–275. [PubMed]
  • Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989 Sep 9;2(8663):588–591. [PubMed]
  • Chang C, Enders G, Sprengel R, Peters N, Varmus HE, Ganem D. Expression of the precore region of an avian hepatitis B virus is not required for viral replication. J Virol. 1987 Oct;61(10):3322–3325. [PMC free article] [PubMed]
  • Enders GH, Ganem D, Varmus H. Mapping the major transcripts of ground squirrel hepatitis virus: the presumptive template for reverse transcriptase is terminally redundant. Cell. 1985 Aug;42(1):297–308. [PubMed]
  • Fagan EA, Smith PM, Davison F, Williams R. Fulminant hepatitis B in successive female sexual partners of two anti-HBe-positive males. Lancet. 1986 Sep 6;2(8506):538–540. [PubMed]
  • Fan H, Chute H, Chao E, Feuerman M. Construction and characterization of Moloney murine leukemia virus mutants unable to synthesize glycosylated gag polyprotein. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5965–5969. [PubMed]
  • Fujiyama A, Miyanohara A, Nozaki C, Yoneyama T, Ohtomo N, Matsubara K. Cloning and structural analyses of hepatitis B virus DNAs, subtype adr. Nucleic Acids Res. 1983 Jul 11;11(13):4601–4610. [PMC free article] [PubMed]
  • Hadziyannis SJ, Lieberman HM, Karvountzis GG, Shafritz DA. Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg Vs. anti-HBe positive carriers of hepatitis B virus. Hepatology. 1983 Sep-Oct;3(5):656–662. [PubMed]
  • Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S. Rapid evolution of RNA genomes. Science. 1982 Mar 26;215(4540):1577–1585. [PubMed]
  • Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med. 1981 Jun;94(6):744–748. [PubMed]
  • Kaneko S, Miller RH, Feinstone SM, Unoura M, Kobayashi K, Hattori N, Purcell RH. Detection of serum hepatitis B virus DNA in patients with chronic hepatitis using the polymerase chain reaction assay. Proc Natl Acad Sci U S A. 1989 Jan;86(1):312–316. [PubMed]
  • McLachlan A, Milich DR, Raney AK, Riggs MG, Hughes JL, Sorge J, Chisari FV. Expression of hepatitis B virus surface and core antigens: influences of pre-S and precore sequences. J Virol. 1987 Mar;61(3):683–692. [PMC free article] [PubMed]
  • Möröy T, Etiemble J, Trépo C, Tiollais P, Buendia MA. Transcription of woodchuck hepatitis virus in the chronically infected liver. EMBO J. 1985 Jun;4(6):1507–1514. [PubMed]
  • Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med. 1976 Apr 1;294(14):746–749. [PubMed]
  • 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 Aug;57(4):231–236. [PubMed]
  • Okamoto H, Imai M, Shimozaki M, Hoshi Y, Iizuka H, Gotanda T, Tsuda F, Miyakawa Y, Mayumi M. Nucleotide sequence of a cloned hepatitis B virus genome, subtype ayr: comparison with genomes of the other three subtypes. J Gen Virol. 1986 Nov;67(Pt 11):2305–2314. [PubMed]
  • Okamoto H, Imai M, Tsuda F, Tanaka T, Miyakawa Y, Mayumi M. Point mutation in the S gene of hepatitis B virus for a d/y or w/r subtypic change in two blood donors carrying a surface antigen of compound subtype adyr or adwr. J Virol. 1987 Oct;61(10):3030–3034. [PMC free article] [PubMed]
  • Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988 Oct;69(Pt 10):2575–2583. [PubMed]
  • Oren I, Hershow RC, Ben-Porath E, Krivoy N, Goldstein N, Rishpon S, Shouval D, Hadler SC, Alter MJ, Maynard JE, et al. A common-source outbreak of fulminant hepatitis B in a hospital. Ann Intern Med. 1989 May 1;110(9):691–698. [PubMed]
  • Ou JH, Laub O, Rutter WJ. Hepatitis B virus gene function: the precore region targets the core antigen to cellular membranes and causes the secretion of the e antigen. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1578–1582. [PubMed]
  • Pasek M, Goto T, Gilbert W, Zink B, Schaller H, MacKay P, Leadbetter G, Murray K. Hepatitis B virus genes and their expression in E. coli. Nature. 1979 Dec 6;282(5739):575–579. [PubMed]
  • Realdi G, Alberti A, Rugge M, Bortolotti F, Rigoli AM, Tremolada F, Ruol A. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology. 1980 Aug;79(2):195–199. [PubMed]
  • Roossinck MJ, Jameel S, Loukin SH, Siddiqui A. Expression of hepatitis B viral core region in mammalian cells. Mol Cell Biol. 1986 May;6(5):1393–1400. [PMC free article] [PubMed]
  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • Schlicht HJ, Salfeld J, Schaller H. The duck hepatitis B virus pre-C region encodes a signal sequence which is essential for synthesis and secretion of processed core proteins but not for virus formation. J Virol. 1987 Dec;61(12):3701–3709. [PMC free article] [PubMed]
  • Schwartzberg P, Colicelli J, Goff SP. Deletion mutants of Moloney murine leukemia virus which lack glycosylated gag protein are replication competent. J Virol. 1983 May;46(2):538–546. [PMC free article] [PubMed]
  • Scotto J, Hadchouel M, Hery C, Yvart J, Tiollais P, Brechot C. Detection of hepatitis B virus DNA in serum by a simple spot hybridization technique: comparison with results for other viral markers. Hepatology. 1983 May-Jun;3(3):279–284. [PubMed]
  • Standring DN, Ou JH, Masiarz FR, Rutter WJ. A signal peptide encoded within the precore region of hepatitis B virus directs the secretion of a heterogeneous population of e antigens in Xenopus oocytes. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8405–8409. [PubMed]
  • Steinhauer DA, Holland JJ. Direct method for quantitation of extreme polymerase error frequencies at selected single base sites in viral RNA. J Virol. 1986 Jan;57(1):219–228. [PMC free article] [PubMed]
  • Summers J, Mason WS. Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell. 1982 Jun;29(2):403–415. [PubMed]
  • Takahashi K, Akahane Y, Gotanda T, Mishiro T, Imai M, Miyakawa Y, Mayumi M. Demonstration of hepatitis B e antigen in the core of Dane particles. J Immunol. 1979 Jan;122(1):275–279. [PubMed]
  • Takahashi K, Machida A, Funatsu G, Nomura M, Usuda S, Aoyagi S, Tachibana K, Miyamoto H, Imai M, Nakamura T, et al. Immunochemical structure of hepatitis B e antigen in the serum. J Immunol. 1983 Jun;130(6):2903–2907. [PubMed]
  • Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. [PubMed]
  • Uy A, Bruss V, Gerlich WH, Köchel HG, Thomssen R. Precore sequence of hepatitis B virus inducing e antigen and membrane association of the viral core protein. Virology. 1986 Nov;155(1):89–96. [PubMed]
  • Vaudin M, Wolstenholme AJ, Tsiquaye KN, Zuckerman AJ, Harrison TJ. The complete nucleotide sequence of the genome of a hepatitis B virus isolated from a naturally infected chimpanzee. J Gen Virol. 1988 Jun;69(Pt 6):1383–1389. [PubMed]
  • Will H, Kuhn C, Cattaneo R, Schaller H. Structure and function of the hepatitis B virus genome. Princess Takamatsu Symp. 1982;12:237–247. [PubMed]
  • Zelent AZ, Sells MA, Price PM, Mohamad A, Acs G, Christman JK. Murine cells carrying integrated tandem genomes of hepatitis B virus DNA transcribe RNAs from endogenous promoters on both viral strands and express middle and major viral envelope proteins. J Virol. 1987 Apr;61(4):1108–1115. [PMC free article] [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)