Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1994 Apr;68(4):2671–2676. doi: 10.1128/jvi.68.4.2671-2676.1994

Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen.

K Yamamoto 1, M Horikita 1, F Tsuda 1, K Itoh 1, Y Akahane 1, S Yotsumoto 1, H Okamoto 1, Y Miyakawa 1, M Mayumi 1
PMCID: PMC236744  PMID: 8139044

Abstract

Hepatitis B virus (HBV) DNA was extracted from sera of six carriers with hepatitis B e antigen as well as antibody to hepatitis B surface antigen and sequenced within the pre-S regions and the S gene. HBV DNA clones from five of these carriers had point mutations in the S gene, resulting in conversion from Ile-126 or Thr-126 of the wild-type virus to Ser-126 or Asn-126 in three carriers and conversion from Gly-145 to Arg-145 in three of them; clones with Asn-126 or Arg-145 were found in one carrier. All 12 clones from the other carrier had an insertion of 24 bp encoding an additional eight amino acids between Thr-123 and Cys-124. In addition, all or at least some of the HBV DNA clones from these carriers had in-phase deletions in the 5' terminus of the pre-S2 region. These results indicate that HBV escape mutants with mutations in the S gene affecting the expression of group-specific determinants would survive in some carriers after they seroconvert to antibody against surface antigen. Carriers with HBV escape mutants may transmit HBV either by donation of blood units without detectable surface antigen or through community-acquired infection, which would hardly be prevented by current hepatitis B immuneglobulin or vaccines.

Full text

PDF
2671

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brown S. E., Howard C. R., Zuckerman A. J., Steward M. W. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet. 1984 Jul 28;2(8396):184–187. doi: 10.1016/s0140-6736(84)90479-3. [DOI] [PubMed] [Google Scholar]
  2. Carman W. F., Jacyna M. R., Hadziyannis S., Karayiannis P., McGarvey M. J., Makris A., Thomas H. C. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989 Sep 9;2(8663):588–591. doi: 10.1016/s0140-6736(89)90713-7. [DOI] [PubMed] [Google Scholar]
  3. Carman W. F., Zanetti A. R., Karayiannis P., Waters J., Manzillo G., Tanzi E., Zuckerman A. J., Thomas H. C. Vaccine-induced escape mutant of hepatitis B virus. Lancet. 1990 Aug 11;336(8711):325–329. doi: 10.1016/0140-6736(90)91874-a. [DOI] [PubMed] [Google Scholar]
  4. Fernholz D., Galle P. R., Stemler M., Brunetto M., Bonino F., Will H. Infectious hepatitis B virus variant defective in pre-S2 protein expression in a chronic carrier. Virology. 1993 May;194(1):137–148. doi: 10.1006/viro.1993.1243. [DOI] [PubMed] [Google Scholar]
  5. Fujii H., Moriyama K., Sakamoto N., Kondo T., Yasuda K., Hiraizumi Y., Yamazaki M., Sakaki Y., Okochi K., Nakajima E. Gly145 to Arg substitution in HBs antigen of immune escape mutant of hepatitis B virus. Biochem Biophys Res Commun. 1992 May 15;184(3):1152–1157. doi: 10.1016/s0006-291x(05)80003-8. [DOI] [PubMed] [Google Scholar]
  6. Gerken G., Kremsdorf D., Capel F., Petit M. A., Dauguet C., Manns M. P., Meyer zum Büschenfelde K. H., Brechot C. Hepatitis B defective virus with rearrangements in the preS gene during chronic HBV infection. Virology. 1991 Aug;183(2):555–565. doi: 10.1016/0042-6822(91)90984-j. [DOI] [PubMed] [Google Scholar]
  7. Harrison T. J., Hopes E. A., Oon C. J., Zanetti A. R., Zuckerman A. J. Independent emergence of a vaccine-induced escape mutant of hepatitis B virus. J Hepatol. 1991;13 (Suppl 4):S105–S107. doi: 10.1016/0168-8278(91)90037-c. [DOI] [PubMed] [Google Scholar]
  8. Hoofnagle J. H., Schafer D. F. Serologic markers of hepatitis B virus infection. Semin Liver Dis. 1986 Feb;6(1):1–10. doi: 10.1055/s-2008-1040787. [DOI] [PubMed] [Google Scholar]
  9. Iizuka H., Ohmura K., Ishijima A., Satoh K., Tanaka T., Tsuda F., Okamoto H., Miyakawa Y., Mayumi M. Correlation between anti-HBc titers and HBV DNA in blood units without detectable HBsAg. Vox Sang. 1992;63(2):107–111. doi: 10.1111/j.1423-0410.1992.tb02495.x. [DOI] [PubMed] [Google Scholar]
  10. McLachlan A., Milich D. R., Raney A. K., Riggs M. G., Hughes J. L., Sorge J., Chisari F. V. Expression of hepatitis B virus surface and core antigens: influences of pre-S and precore sequences. J Virol. 1987 Mar;61(3):683–692. doi: 10.1128/jvi.61.3.683-692.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McMahon G., Ehrlich P. H., Moustafa Z. A., McCarthy L. A., Dottavio D., Tolpin M. D., Nadler P. I., Ostberg L. Genetic alterations in the gene encoding the major HBsAg: DNA and immunological analysis of recurrent HBsAg derived from monoclonal antibody-treated liver transplant patients. Hepatology. 1992 May;15(5):757–766. doi: 10.1002/hep.1840150503. [DOI] [PubMed] [Google Scholar]
  12. Moriyama K., Nakajima E., Hohjoh H., Asayama R., Okochi K. Immunoselected hepatitis B virus mutant. Lancet. 1991 Jan 12;337(8733):125–125. doi: 10.1016/0140-6736(91)90793-o. [DOI] [PubMed] [Google Scholar]
  13. Neurath A. R., Kent S. B., Strick N., Taylor P., Stevens C. E. Hepatitis B virus contains pre-S gene-encoded domains. Nature. 1985 May 9;315(6015):154–156. doi: 10.1038/315154a0. [DOI] [PubMed] [Google Scholar]
  14. Ohnuma H., Machida A., Okamoto H., Tsuda F., Sakamoto M., Tanaka T., Miyakawa Y., Mayumi M. Allelic subtypic determinants of hepatitis B surface antigen (i and t) that are distinct from d/y or w/r. J Virol. 1993 Feb;67(2):927–932. doi: 10.1128/jvi.67.2.927-932.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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. doi: 10.1056/NEJM197604012941402. [DOI] [PubMed] [Google Scholar]
  16. 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] [Google Scholar]
  17. Okamoto H., Imai M., Usuda S., Tanaka E., Tachibana K., Mishiro S., Machida A., Nakamura T., Miyakawa Y., Mayumi M. Hemagglutination assay of polypeptide coded by the pre-S region of hepatitis B virus DNA with monoclonal antibody: correlation of pre-S polypeptide with the receptor for polymerized human serum albumin in serums containing hepatitis B antigens. J Immunol. 1985 Feb;134(2):1212–1216. [PubMed] [Google Scholar]
  18. Okamoto H., Usuda S., Imai M., Tachibana K., Tanaka E., Kumakura T., Itabashi M., Takai E., Tsuda F., Nakamura T. Antibody to the receptor for polymerized human serum albumin in acute and persistent infection with hepatitis B virus. Hepatology. 1986 May-Jun;6(3):354–359. doi: 10.1002/hep.1840060304. [DOI] [PubMed] [Google Scholar]
  19. Okamoto H., Yano K., Nozaki Y., Matsui A., Miyazaki H., Yamamoto K., Tsuda F., Machida A., Mishiro S. Mutations within the S gene of hepatitis B virus transmitted from mothers to babies immunized with hepatitis B immune globulin and vaccine. Pediatr Res. 1992 Sep;32(3):264–268. doi: 10.1203/00006450-199209000-00002. [DOI] [PubMed] [Google Scholar]
  20. Okamoto H., Yotsumoto S., Akahane Y., Yamanaka T., Miyazaki Y., Sugai Y., Tsuda F., Tanaka T., Miyakawa Y., Mayumi M. Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol. 1990 Mar;64(3):1298–1303. doi: 10.1128/jvi.64.3.1298-1303.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Paterlini P., Gerken G., Nakajima E., Terre S., D'Errico A., Grigioni W., Nalpas B., Franco D., Wands J., Kew M. Polymerase chain reaction to detect hepatitis B virus DNA and RNA sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl J Med. 1990 Jul 12;323(2):80–85. doi: 10.1056/NEJM199007123230202. [DOI] [PubMed] [Google Scholar]
  22. 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 Feb;64(2):613–620. doi: 10.1128/jvi.64.2.613-620.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Santantonio T., Jung M. C., Schneider R., Fernholz D., Milella M., Monno L., Pastore G., Pape G. R., Will H. Hepatitis B virus genomes that cannot synthesize pre-S2 proteins occur frequently and as dominant virus populations in chronic carriers in Italy. Virology. 1992 Jun;188(2):948–952. doi: 10.1016/0042-6822(92)90559-8. [DOI] [PubMed] [Google Scholar]
  24. Schaller H., Fischer M. Transcriptional control of hepadnavirus gene expression. Curr Top Microbiol Immunol. 1991;168:21–39. doi: 10.1007/978-3-642-76015-0_2. [DOI] [PubMed] [Google Scholar]
  25. Schödel F., Moriarty A. M., Peterson D. L., Zheng J. A., Hughes J. L., Will H., Leturcq D. J., McGee J. S., Milich D. R. The position of heterologous epitopes inserted in hepatitis B virus core particles determines their immunogenicity. J Virol. 1992 Jan;66(1):106–114. doi: 10.1128/jvi.66.1.106-114.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Steinhauer D. A., Holland J. J. 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. doi: 10.1128/jvi.57.1.219-228.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Summers J., Mason W. S. Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell. 1982 Jun;29(2):403–415. doi: 10.1016/0092-8674(82)90157-x. [DOI] [PubMed] [Google Scholar]
  28. Takahashi K., Kishimoto S., Ohnuma H., Machida A., Takai E., Tsuda F., Miyamoto H., Tanaka T., Matsushita K., Oda K. Polypeptides coded for by the region pre-S and gene S of hepatitis B virus DNA with the receptor for polymerized human serum albumin: expression on hepatitis B particles produced in the HBeAg or anti-HBe phase of hepatitis B virus infection. J Immunol. 1986 May 1;136(9):3467–3472. [PubMed] [Google Scholar]
  29. Thiers V., Nakajima E., Kremsdorf D., Mack D., Schellekens H., Driss F., Goudeau A., Wands J., Sninsky J., Tiollais P. Transmission of hepatitis B from hepatitis-B-seronegative subjects. Lancet. 1988 Dec 3;2(8623):1273–1276. doi: 10.1016/s0140-6736(88)92891-7. [DOI] [PubMed] [Google Scholar]
  30. Tiollais P., Pourcel C., Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. doi: 10.1038/317489a0. [DOI] [PubMed] [Google Scholar]
  31. Uy A., Bruss V., Gerlich W. H., Köchel H. G., 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. doi: 10.1016/0042-6822(86)90170-4. [DOI] [PubMed] [Google Scholar]

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

RESOURCES