Abstract
Cytotoxic T lymphocytes (CTL) are thought to control hepatitis B virus (HBV) infection, since they are readily detectable in patients who clear the virus whereas they are hard to detect during chronic HBV infection. In chronic hepatitis C virus (HCV) infection, however, the virus persists in the face of a CTL response. Indeed, most infected patients respond to one or more HCV-1 (genotype 1a)-derived CTL epitopes in the core, NS3, and NS4 proteins, and the CTL response is equally strong in patients infected by different HCV genotypes, suggesting broad cross-reactivity. To examine the effect of the HCV-specific CTL response in patients with chronic hepatitis C on viral load and disease activity, we quantitated the strength of the multispecific CTL response against 10 independent epitopes within the HCV polyprotein. We could not detect a linear correlation between the CTL response and viral load or disease activity in these patients. However, the CTL response was stronger in the subgroup of patients whose HCV RNA was below the detection threshold of the HCV branched- chain DNA assay than in branched-chain-DNA-positive patients. These results suggest that the HCV-specific CTL response may be able to control viral load to some extent in chronically infected patients, and they indicate that prospective studies in acutely infected patients who successfully clear HCV should be performed to more precisely define the relationship between CTL responsiveness, viral clearance, and disease severity in this infection.
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- Alter M. J., Gerety R. J., Smallwood L. A., Sampliner R. E., Tabor E., Deinhardt F., Frösner G., Matanoski G. M. Sporadic non-A, non-B hepatitis: frequency and epidemiology in an urban U.S. population. J Infect Dis. 1982 Jun;145(6):886–893. doi: 10.1093/infdis/145.6.886. [DOI] [PubMed] [Google Scholar]
- Alter M. J., Hadler S. C., Judson F. N., Mares A., Alexander W. J., Hu P. Y., Miller J. K., Moyer L. A., Fields H. A., Bradley D. W. Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA. 1990 Nov 7;264(17):2231–2235. [PubMed] [Google Scholar]
- 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]
- Battegay M., Fikes J., Di Bisceglie A. M., Wentworth P. A., Sette A., Celis E., Ching W. M., Grakoui A., Rice C. M., Kurokohchi K. Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules. J Virol. 1995 Apr;69(4):2462–2470. doi: 10.1128/jvi.69.4.2462-2470.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bertoletti A., Ferrari C., Fiaccadori F., Penna A., Margolskee R., Schlicht H. J., Fowler P., Guilhot S., Chisari F. V. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10445–10449. doi: 10.1073/pnas.88.23.10445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Borysiewicz L. K., Morris S., Page J. D., Sissons J. G. Human cytomegalovirus-specific cytotoxic T lymphocytes: requirements for in vitro generation and specificity. Eur J Immunol. 1983 Oct;13(10):804–809. doi: 10.1002/eji.1830131005. [DOI] [PubMed] [Google Scholar]
- Carmichael A., Jin X., Sissons P., Borysiewicz L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J Exp Med. 1993 Feb 1;177(2):249–256. doi: 10.1084/jem.177.2.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cerny A., McHutchison J. G., Pasquinelli C., Brown M. E., Brothers M. A., Grabscheid B., Fowler P., Houghton M., Chisari F. V. Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif. J Clin Invest. 1995 Feb;95(2):521–530. doi: 10.1172/JCI117694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chan S. W., McOmish F., Holmes E. C., Dow B., Peutherer J. F., Follett E., Yap P. L., Simmonds P. Analysis of a new hepatitis C virus type and its phylogenetic relationship to existing variants. J Gen Virol. 1992 May;73(Pt 5):1131–1141. doi: 10.1099/0022-1317-73-5-1131. [DOI] [PubMed] [Google Scholar]
- Chisari F. V., Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol. 1995;13:29–60. doi: 10.1146/annurev.iy.13.040195.000333. [DOI] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Fleischer B., Kreth H. W. Clonal expansion and functional analysis of virus-specific T lymphocytes from cerebrospinal fluid in measles encephalitis. Hum Immunol. 1983 Aug;7(4):239–248. doi: 10.1016/0198-8859(83)90061-7. [DOI] [PubMed] [Google Scholar]
- Guidotti L. G., Ishikawa T., Hobbs M. V., Matzke B., Schreiber R., Chisari F. V. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996 Jan;4(1):25–36. doi: 10.1016/s1074-7613(00)80295-2. [DOI] [PubMed] [Google Scholar]
- Koziel M. J., Dudley D., Afdhal N., Choo Q. L., Houghton M., Ralston R., Walker B. D. Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV. J Virol. 1993 Dec;67(12):7522–7532. doi: 10.1128/jvi.67.12.7522-7532.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koziel M. J., Dudley D., Wong J. T., Dienstag J., Houghton M., Ralston R., Walker B. D. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol. 1992 Nov 15;149(10):3339–3344. [PubMed] [Google Scholar]
- Nayersina R., Fowler P., Guilhot S., Missale G., Cerny A., Schlicht H. J., Vitiello A., Chesnut R., Person J. L., Redeker A. G. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol. 1993 May 15;150(10):4659–4671. [PubMed] [Google Scholar]
- 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. doi: 10.1038/282575a0. [DOI] [PubMed] [Google Scholar]
- Rehermann B., Fowler P., Sidney J., Person J., Redeker A., Brown M., Moss B., Sette A., Chisari F. V. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med. 1995 Mar 1;181(3):1047–1058. doi: 10.1084/jem.181.3.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shirai M., Arichi T., Nishioka M., Nomura T., Ikeda K., Kawanishi K., Engelhard V. H., Feinstone S. M., Berzofsky J. A. CTL responses of HLA-A2.1-transgenic mice specific for hepatitis C viral peptides predict epitopes for CTL of humans carrying HLA-A2.1. J Immunol. 1995 Mar 15;154(6):2733–2742. [PubMed] [Google Scholar]
- Stuyver L., Wyseur A., van Arnhem W., Lunel F., Laurent-Puig P., Pawlotsky J. M., Kleter B., Bassit L., Nkengasong J., van Doorn L. J. Hepatitis C virus genotyping by means of 5'-UR/core line probe assays and molecular analysis of untypeable samples. Virus Res. 1995 Oct;38(2-3):137–157. doi: 10.1016/0168-1702(95)00052-r. [DOI] [PubMed] [Google Scholar]
- Varki A. P. The times they are still a'changing: keeping up with the times. J Clin Invest. 1996 Jan 1;97(1):1–1. doi: 10.1172/JCI118375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiner A., Erickson A. L., Kansopon J., Crawford K., Muchmore E., Hughes A. L., Houghton M., Walker C. M. Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2755–2759. doi: 10.1073/pnas.92.7.2755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yano A., Aosai F., Ohta M., Hasekura H., Sugane K., Hayashi S. Antigen presentation by Toxoplasma gondii-infected cells to CD4+ proliferative T cells and CD8+ cytotoxic cells. J Parasitol. 1989 Jun;75(3):411–416. [PubMed] [Google Scholar]