Analysis of Successful Immune Responses in Persons Infected with Hepatitis C Virus

Journal of Experimental Medicine - Tập 191 Số 9 - Trang 1499-1512 - 2000
Franziska Lechner1, David Wong2, P. Rod Dunbar3, R W Chapman1, Raymond T. Chung4, Paul B. Dohrenwend2, Gregory K. Robbins2, Rodney E. Phillips1, Paul Klenerman1, Bruce D. Walker2
1Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom
2cInfectious Disease Unit and AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129
3bMedical Research Council Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom
4dGastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129

Tóm tắt

Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a “stunned” phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.

Từ khóa


Tài liệu tham khảo

Cohen, 1999, The scientific challenge of hepatitis C virus, Science., 285, 26, 10.1126/science.285.5424.26

Koziel, 1995, HLA class I–restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release, J. Clin. Invest., 96, 2311, 10.1172/JCI118287

Rehermann, 1996, Differential CTL responsiveness to hepatitis B and C viruses in chronically infected patients, J. Virol., 70, 7092, 10.1128/jvi.70.10.7092-7102.1996

Rehermann, 1996, Quantitative analysis of the peripheral blood CTL response in patients with chronic HCV infection, J. Clin. Invest., 98, 1432, 10.1172/JCI118931

Cerny, 1995, CTL response to HCV-derived peptides containing the HLA-A2.1 binding motif, J. Clin. Invest., 95, 521, 10.1172/JCI117694

Cerny, 1995, Induction in vitro of a primary human antiviral cytotoxic T cell response, Eur. J. Immunol., 25, 627, 10.1002/eji.1830250248

Hiroishi, 1997, Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection, Hepatology., 25, 705, 10.1002/hep.510250336

Wong, 1998, Liver-derived CTL in hepatitis C virus infectionbreadth and specificity of responses in a cohort of persons with chronic infection, J. Immunol., 160, 1479, 10.4049/jimmunol.160.3.1479

Giuggio, 1998, Inefficient recognition of autologous viral sequences by intrahepatic HCV-specific CTL in chronically infected subjects, Virology., 251, 132, 10.1006/viro.1998.9401

He, 1999, Quantitative analysis of HCV-specific CD8+ T cells in peripheral blood and liver using peptide-MHC tetramers, Proc. Natl. Acad. Sci. USA., 96, 5692, 10.1073/pnas.96.10.5692

Koup, 1994, Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome, J. Virol., 68, 4650, 10.1128/jvi.68.7.4650-4655.1994

Watson, 1997, Early postinfection antiviral treatment reduces viral load and prevents CD4+ cell decline in HIV type 2-infected macaques, AIDS Res. Hum. Retroviruses., 13, 1375, 10.1089/aid.1997.13.1375

Maini, 1999, Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection, Gastroenterology., 117, 1386, 10.1016/S0016-5085(99)70289-1

Lisziewicz, 1999, Control of HIV despite the discontinuation of antiretroviral therapy, N. Engl. J. Med., 340, 1683, 10.1056/NEJM199905273402114

Pantaleo, 1997, The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viraemia, Proc. Natl. Acad. Sci. USA., 94, 254, 10.1073/pnas.94.1.254

Hay, 1999, Lack of viral escape and defective in vivo activation of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes in rapidly progressive infection, J. Virol., 73, 5509, 10.1128/JVI.73.7.5509-5519.1999

Guidotti, 1996, Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes, Immunity., 4, 25, 10.1016/S1074-7613(00)80295-2

Yang, 1997, Suppression of human immunodeficiency virus type 1 replication by CD8+ cellsevidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms, J. Virol., 71, 3120, 10.1128/jvi.71.4.3120-3128.1997

Guidotti, 1999, Viral clearance without destruction of infected cells during acute HBV infection, Science., 284, 825, 10.1126/science.284.5415.825

Koziel, 1999, Cytokines in viral hepatitis, Semin. Liver Dis., 19, 157, 10.1055/s-2007-1007107

Planz, 1997, A critical role for neutralizing antibody-producing B cells, CD4+ cells and interferons in persistent infections of mice with LCMVimplications for adoptive immunotherapy of virus carriers, Proc. Natl. Acad. Sci. USA., 94, 6874, 10.1073/pnas.94.13.6874

Zajac, 1998, Viral immune evasion due to persistence of activated T cells without effector function, J. Exp. Med., 188, 2205, 10.1084/jem.188.12.2205

Diepolder, 1995, Possible mechanism involving T lymphocyte response to NS3 in viral clearance in acute HCV infection, Lancet., 346, 1006, 10.1016/S0140-6736(95)91691-1

Missale, 1996, Different clinical behaviors of acute HCV infection are associated with different vigor of the anti-viral T cell response, J. Clin. Invest., 98, 706, 10.1172/JCI118842

Cooper, 1999, Analysis of a successful immune response against HCV, Immunity., 10, 439, 10.1016/S1074-7613(00)80044-8

Gallimore, 1998, Induction and exhaustion of lymphocytic choriomeningitis virus–specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I–peptide complexes, J. Exp. Med., 187, 1383, 10.1084/jem.187.9.1383

Murali-Krishna, 1998, Counting antigen-specific CD8 T cellsa reevaluation of bystander activation during viral infection, Immunity., 8, 177, 10.1016/S1074-7613(00)80470-7

Lee, 1999, Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients, Nat. Med., 5, 677, 10.1038/9525

Lubaki, 1994, A novel method for detection and ex vivo expansion of HIV type 1-specific cytolytic T lymphocytes, AIDS Res. Hum. Retroviruses., 10, 1427, 10.1089/aid.1994.10.1427

Grakoui, 1993, Expression and identification of hepatitis C virus polyprotein cleavage products, J. Virol., 67, 1385, 10.1128/jvi.67.3.1385-1395.1993

Altman, 1996, Direct visualization and phenotypic analysis of virus-specific T lymphocytes in HIV-infected individuals, Science., 274, 94, 10.1126/science.274.5284.94

Battegay, 1995, 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., 69, 2462, 10.1128/jvi.69.4.2462-2470.1995

Callan, 1998, Direct visualization of antigen-specific CD8+ T cells during the primary immune response to EBV in vivo, J. Exp. Med., 187, 1395, 10.1084/jem.187.9.1395

Dunbar, 1998, Direct isolation, phenotyping and cloning of low-frequency antigen-specific cytotoxic T lymphocytes from peripheral blood, Curr. Biol., 8, 413, 10.1016/S0960-9822(98)70161-7

Rammensee, 1993, Peptides naturally presented by MHC class I molecules, Annu. Rev. Immunol., 11, 213, 10.1146/annurev.iy.11.040193.001241

Klenerman, 1996, Identification of a novel A-25 restricted epitope in a conserved region of p24 gag (positions 71–80), AIDS., 10, 348, 10.1097/00002030-199603000-00023

Cerwenka, 1999, Migration kinetics and final destination of type 1 and type 2 CD8 effector cells predict protection against pulmonary virus infection, J. Exp. Med., 189, 423, 10.1084/jem.189.2.423

Moskophidis, 1993, Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells, Nature., 362, 758, 10.1038/362758a0

Valitutti, 1995, Serial triggering of many T cell receptors by a few peptide-MHC complexes, Nature., 375, 148, 10.1038/375148a0

Viola, 1996, T cell activation determined by TCR number and tunable thresholds, Science., 273, 104, 10.1126/science.273.5271.104

Viola, 1997, Quantitative contribution of CD4 and CD8 to T cell antigen receptor serial triggering, J. Exp. Med., 186, 1775, 10.1084/jem.186.10.1775

Busch, 1998, Coordinate regulation of complex T cell populations responding to bacterial infection, Immunity., 8, 353, 10.1016/S1074-7613(00)80540-3

Gerlach, 1999, Recurrence of HCV after loss of virus specific CD4+ T cell response in acute hepatitis C, Gastroenterology., 117, 933, 10.1016/S0016-5085(99)70353-7

Minutello, 1993, Compartmentalization of T lymphocytes to the site of diseaseintrahepatic T cells specific for the NS4 protein of hepatitis C virus in patients with chronic hepatitis C, J. Exp. Med., 178, 17, 10.1084/jem.178.1.17

Zinkernagel, 1993, Effector T-cell induction and T-cell memory versus peripheral deletion of T cells, Immunol. Rev., 133, 199, 10.1111/j.1600-065X.1993.tb01517.x

Borrow, 1997, Antiviral pressure exerted by HIV-1 specific CTL during primary infection demonstrated by rapid selection of CTL escape virus, Nat. Med., 3, 205, 10.1038/nm0297-205

Ogg, 1998, Quantitation of HIV-1 specific CTL and plasma load of HIV-1, Science., 279, 2103, 10.1126/science.279.5359.2103

Sallusto, 1999, Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, Nature., 401, 708, 10.1038/44385

Evavold, 1991, Separation of IL-4 production from proliferation by an altered peptide ligand, Science., 252, 1308, 10.1126/science.1833816

Moskophidis, 1994, MHC class I and non-MHC-linked capacity for generating an anti-viral CTL response determines susceptibility to CTL exhaustion and establishment of virus persistence in mice, J. Immunol., 152, 4976, 10.4049/jimmunol.152.10.4976

Mehal, 1999, Selective retention of activated CD8+ T cells by the normal liver, J. Immunol., 163, 3202, 10.4049/jimmunol.163.6.3202

Naoumov, 1999, HCV specific CD4+ T cellsdo they help or damage?, Gastroenterology., 117, 1012, 10.1016/S0016-5085(99)70361-6

Weiland, 1998, Can HCV infection be cleared?, Lancet., 352, 668, 10.1016/S0140-6736(05)60815-X

Dries, 1999, Detection of hepatitis C virus in paraffin-embedded liver biopsies of patients negative for viral RNA in serum, Hepatology., 29, 223, 10.1002/hep.510290118

Kaufmann, 1999, Phenotypic analysis of CD8+ T lymphocytes in a cohort of HIV-1 infected patients treated with saquinavir, ritonavir and two nucleoside analogues for 1 year and association with plasma HIV-1 RNA, AIDS Res. Hum. Retroviruses., 15, 963, 10.1089/088922299310476

Kalams, 1999, Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy, J. Virol., 73, 6721, 10.1128/JVI.73.8.6721-6728.1999

Giorgi, 1993, Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levelsresults of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study, J. Acquir. Immune Defic. Syndr., 6, 904

Valiante, 2000, Life, activation and death of intra-hepatic lymphocytes in chronic viral hepatitis, Immunol. Rev, In press

Chang, 1997, Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus, J. Clin. Invest., 100, 2376, 10.1172/JCI119778

Klenerman, 1996, Cytotoxic T cell antagonism in HIV, Semin. Virol., 7, 31, 10.1006/smvy.1996.0005

Tsai, 1998, Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity, Gastroenterology., 115, 954, 10.1016/S0016-5085(98)70268-9

Moskophidis, 1995, Immunobiology of cytotoxic T-cell escape mutants of lymphocytic choriomeningitis virus, J. Virol., 69, 2187, 10.1128/jvi.69.4.2187-2193.1995

Weiner, 1995, Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant, Proc. Natl. Acad. Sci. USA., 92, 2755, 10.1073/pnas.92.7.2755

Thông tin
Thông tin xuất bản

Journal of Experimental Medicine

Tập 191 Số 9

1499-1512

Thông tin tác giả