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. 1994 Aug 2;91(16):7792–7796. doi: 10.1073/pnas.91.16.7792

Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization.

P Farci 1, H J Alter 1, D C Wong 1, R H Miller 1, S Govindarajan 1, R Engle 1, M Shapiro 1, R H Purcell 1
PMCID: PMC44488  PMID: 7519785

Abstract

Hepatitis C virus (HCV) is the most important etiologic agent of non-A, non-B hepatitis and is a major cause of chronic liver disease and hepatocellular carcinoma. Development of an effective vaccine would be the most practical method for prevention of the infection, but whether infection with HCV elicits protective immunity in the host is unclear. Neutralization of HCV in vitro was attempted with plasma of a chronically infected patient, and the residual infectivity was evaluated by inoculation of eight seronegative chimpanzees. The source of HCV was plasma obtained from a patient during the acute phase of posttransfusion non-A, non-B hepatitis, which had previously been titered for infectivity in chimpanzees. Neutralization was achieved with plasma obtained from the same patient 2 yr after the onset of primary infection but not with plasma obtained 11 yr later, although both plasmas contained antibodies against nonstructural and structural (including envelope) HCV proteins. Analysis of sequential viral isolates from the same patient revealed significant genetic divergence as early as 2 yr after infection. However, the HCV recovered from the patient 2 yr after the infection had a striking sequence similarity with the HCV recovered from one of the chimpanzees inoculated with the acute-phase virus, suggesting that the progenitor of the new strain was already present 2 yr earlier. This evidence, together with the different sequences of HCV recovered from the chimpanzees that received the same inoculum, confirms that HCV is present in vivo as a quasispecies. These results provide experimental evidence in vivo that HCV infection elicits a neutralizing antibody response in humans but suggest that such antibodies are isolate-specific. This result raises concerns for the development of a broadly reactive vaccine against HCV.

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Selected References

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  1. Alter H. J., Purcell R. H., Shih J. W., Melpolder J. C., Houghton M., Choo Q. L., Kuo G. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med. 1989 Nov 30;321(22):1494–1500. doi: 10.1056/NEJM198911303212202. [DOI] [PubMed] [Google Scholar]
  2. Alter M. J., Margolis H. S., Krawczynski K., Judson F. N., Mares A., Alexander W. J., Hu P. Y., Miller J. K., Gerber M. A., Sampliner R. E. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med. 1992 Dec 31;327(27):1899–1905. doi: 10.1056/NEJM199212313272702. [DOI] [PubMed] [Google Scholar]
  3. Bachmann B., Lüke W., Hunsmann G. Improvement of PCR amplified DNA sequencing with the aid of detergents. Nucleic Acids Res. 1990 Mar 11;18(5):1309–1309. doi: 10.1093/nar/18.5.1309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bukh J., Purcell R. H., Miller R. H. At least 12 genotypes of hepatitis C virus predicted by sequence analysis of the putative E1 gene of isolates collected worldwide. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8234–8238. doi: 10.1073/pnas.90.17.8234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chien D. Y., Choo Q. L., Tabrizi A., Kuo C., McFarland J., Berger K., Lee C., Shuster J. R., Nguyen T., Moyer D. L. Diagnosis of hepatitis C virus (HCV) infection using an immunodominant chimeric polyprotein to capture circulating antibodies: reevaluation of the role of HCV in liver disease. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10011–10015. doi: 10.1073/pnas.89.21.10011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Choo Q. L., Kuo G., Ralston R., Weiner A., Chien D., Van Nest G., Han J., Berger K., Thudium K., Kuo C. Vaccination of chimpanzees against infection by the hepatitis C virus. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1294–1298. doi: 10.1073/pnas.91.4.1294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Choo Q. L., Richman K. H., Han J. H., Berger K., Lee C., Dong C., Gallegos C., Coit D., Medina-Selby R., Barr P. J. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2451–2455. doi: 10.1073/pnas.88.6.2451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cichutek K., Merget H., Norley S., Linde R., Kreuz W., Gahr M., Kurth R. Development of a quasispecies of human immunodeficiency virus type 1 in vivo. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7365–7369. doi: 10.1073/pnas.89.16.7365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dienstag J. L. non-A, Non-B hepatitis. II. Experimental transmission, putative virus agents and markers, and prevention. Gastroenterology. 1983 Sep;85(3):743–768. [PubMed] [Google Scholar]
  10. Emini E. A., Nara P. L., Schleif W. A., Lewis J. A., Davide J. P., Lee D. R., Kessler J., Conley S., Matsushita S., Putney S. D. Antibody-mediated in vitro neutralization of human immunodeficiency virus type 1 abolishes infectivity for chimpanzees. J Virol. 1990 Aug;64(8):3674–3678. doi: 10.1128/jvi.64.8.3674-3678.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Farci P., Alter H. J., Govindarajan S., Wong D. C., Engle R., Lesniewski R. R., Mushahwar I. K., Desai S. M., Miller R. H., Ogata N. Lack of protective immunity against reinfection with hepatitis C virus. Science. 1992 Oct 2;258(5079):135–140. doi: 10.1126/science.1279801. [DOI] [PubMed] [Google Scholar]
  12. Farci P., Alter H. J., Wong D., Miller R. H., Shih J. W., Jett B., Purcell R. H. A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med. 1991 Jul 11;325(2):98–104. doi: 10.1056/NEJM199107113250205. [DOI] [PubMed] [Google Scholar]
  13. Farci P., London W. T., Wong D. C., Dawson G. J., Vallari D. S., Engle R., Purcell R. H. The natural history of infection with hepatitis C virus (HCV) in chimpanzees: comparison of serologic responses measured with first- and second-generation assays and relationship to HCV viremia. J Infect Dis. 1992 Jun;165(6):1006–1011. doi: 10.1093/infdis/165.6.1006. [DOI] [PubMed] [Google Scholar]
  14. Feinstone S. M., Alter H. J., Dienes H. P., Shimizu Y., Popper H., Blackmore D., Sly D., London W. T., Purcell R. H. Non-A, non-B hepatitis in chimpanzees and marmosets. J Infect Dis. 1981 Dec;144(6):588–598. doi: 10.1093/infdis/144.6.588. [DOI] [PubMed] [Google Scholar]
  15. Higgins D. G., Sharp P. M. CLUSTAL: a package for performing multiple sequence alignment on a microcomputer. Gene. 1988 Dec 15;73(1):237–244. doi: 10.1016/0378-1119(88)90330-7. [DOI] [PubMed] [Google Scholar]
  16. Hijikata M., Kato N., Ootsuyama Y., Nakagawa M., Ohkoshi S., Shimotohno K. Hypervariable regions in the putative glycoprotein of hepatitis C virus. Biochem Biophys Res Commun. 1991 Feb 28;175(1):220–228. doi: 10.1016/s0006-291x(05)81223-9. [DOI] [PubMed] [Google Scholar]
  17. Horton R. "Renegade" HIV immunity hypothesis gains momentum. Lancet. 1993 Dec 18;342(8886-8887):1545–1545. doi: 10.1016/s0140-6736(05)80106-0. [DOI] [PubMed] [Google Scholar]
  18. Houghton M., Weiner A., Han J., Kuo G., Choo Q. L. Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral disease. Hepatology. 1991 Aug;14(2):381–388. [PubMed] [Google Scholar]
  19. Koziol D. E., Holland P. V., Alling D. W., Melpolder J. C., Solomon R. E., Purcell R. H., Hudson L. M., Shoup F. J., Krakauer H., Alter H. J. Antibody to hepatitis B core antigen as a paradoxical marker for non-A, non-B hepatitis agents in donated blood. Ann Intern Med. 1986 Apr;104(4):488–495. doi: 10.7326/0003-4819-104-4-488. [DOI] [PubMed] [Google Scholar]
  20. Kurosaki M., Enomoto N., Marumo F., Sato C. Rapid sequence variation of the hypervariable region of hepatitis C virus during the course of chronic infection. Hepatology. 1993 Dec;18(6):1293–1299. [PubMed] [Google Scholar]
  21. Lai M. E., Mazzoleni A. P., Argiolu F., De Virgilis S., Balestrieri A., Purcell R. H., Cao A., Farci P. Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet. 1994 Feb 12;343(8894):388–390. doi: 10.1016/s0140-6736(94)91224-6. [DOI] [PubMed] [Google Scholar]
  22. Letvin N. L. Vaccines against human immunodeficiency virus--progress and prospects. N Engl J Med. 1993 Nov 4;329(19):1400–1405. doi: 10.1056/NEJM199311043291908. [DOI] [PubMed] [Google Scholar]
  23. Martell M., Esteban J. I., Quer J., Genescà J., Weiner A., Esteban R., Guardia J., Gómez J. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol. 1992 May;66(5):3225–3229. doi: 10.1128/jvi.66.5.3225-3229.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miller R. H., Purcell R. H. Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2057–2061. doi: 10.1073/pnas.87.6.2057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ogata N., Alter H. J., Miller R. H., Purcell R. H. Nucleotide sequence and mutation rate of the H strain of hepatitis C virus. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3392–3396. doi: 10.1073/pnas.88.8.3392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Okamoto H., Kojima M., Okada S., Yoshizawa H., Iizuka H., Tanaka T., Muchmore E. E., Peterson D. A., Ito Y., Mishiro S. Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. Virology. 1992 Oct;190(2):894–899. doi: 10.1016/0042-6822(92)90933-g. [DOI] [PubMed] [Google Scholar]
  27. Okamoto H., Kurai K., Okada S., Yamamoto K., Lizuka H., Tanaka T., Fukuda S., Tsuda F., Mishiro S. Full-length sequence of a hepatitis C virus genome having poor homology to reported isolates: comparative study of four distinct genotypes. Virology. 1992 May;188(1):331–341. doi: 10.1016/0042-6822(92)90762-e. [DOI] [PubMed] [Google Scholar]
  28. Prince A. M., Brotman B., Huima T., Pascual D., Jaffery M., Inchauspé G. Immunity in hepatitis C infection. J Infect Dis. 1992 Mar;165(3):438–443. doi: 10.1093/infdis/165.3.438. [DOI] [PubMed] [Google Scholar]
  29. Realdi G., Alberti A., Rugge M., Rigoli A. M., Tremolada F., Schivazappa L., Ruol A. Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis. Gut. 1982 Apr;23(4):270–275. doi: 10.1136/gut.23.4.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shimizu Y. K., Hijikata M., Iwamoto A., Alter H. J., Purcell R. H., Yoshikura H. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses. J Virol. 1994 Mar;68(3):1494–1500. doi: 10.1128/jvi.68.3.1494-1500.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Shimizu Y. K., Weiner A. J., Rosenblatt J., Wong D. C., Shapiro M., Popkin T., Houghton M., Alter H. J., Purcell R. H. Early events in hepatitis C virus infection of chimpanzees. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6441–6444. doi: 10.1073/pnas.87.16.6441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Simmonds P., McOmish F., Yap P. L., Chan S. W., Lin C. K., Dusheiko G., Saeed A. A., Holmes E. C. Sequence variability in the 5' non-coding region of hepatitis C virus: identification of a new virus type and restrictions on sequence diversity. J Gen Virol. 1993 Apr;74(Pt 4):661–668. doi: 10.1099/0022-1317-74-4-661. [DOI] [PubMed] [Google Scholar]
  33. Takeuchi K., Boonmar S., Kubo Y., Katayama T., Harada H., Ohbayashi A., Choo Q. L., Kuo G., Houghton M., Saito I. Hepatitis C viral cDNA clones isolated from a healthy carrier donor implicated in post-transfusion non-A, non-B hepatitis. Gene. 1990 Jul 16;91(2):287–291. doi: 10.1016/0378-1119(90)90102-w. [DOI] [PubMed] [Google Scholar]
  34. Weiner A. J., Brauer M. J., Rosenblatt J., Richman K. H., Tung J., Crawford K., Bonino F., Saracco G., Choo Q. L., Houghton M. Variable and hypervariable domains are found in the regions of HCV corresponding to the flavivirus envelope and NS1 proteins and the pestivirus envelope glycoproteins. Virology. 1991 Feb;180(2):842–848. doi: 10.1016/0042-6822(91)90104-j. [DOI] [PubMed] [Google Scholar]
  35. Weiner A. J., Geysen H. M., Christopherson C., Hall J. E., Mason T. J., Saracco G., Bonino F., Crawford K., Marion C. D., Crawford K. A. Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3468–3472. doi: 10.1073/pnas.89.8.3468. [DOI] [PMC free article] [PubMed] [Google Scholar]

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