Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence

Journal of Experimental Medicine

Volumn 209, Issue 1, 2012, Pages 61-75

  Schulze zur Wiesch, Julian ^a,b,c   Ciuffreda, Donatella ^a   Lewis Ximenez, Lia ^f   Kasprowicz, Victoria ^a   Nolan, Brian E ^a   Streeck, Hendrik ^a   Aneja, Jasneet ^a   Reyor, Laura L ^a   Allen, Todd M ^a   Lohse, Ansgar W ^b   McGovern, Barbara ^d   Chung, Raymond T ^a   Kwok, William W ^e   Kim, Arthur Y ^a   Lauer, Georg M ^a  

^a MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^b UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^c LEIBNIZ INSTITUTE FOR EXPERIMENTAL VIROLOGY   (Germany)

^d LEMUEL SHATTUCK HOSPITAL   (United States)

^e BENAROYA RESEARCH INSTITUTE   (United States)

^f INSTITUTO OSWALDO CRUZ   (Brazil)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; GAMMA INTERFERON; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; RECOMBINANT INTERLEUKIN 2; TETRAMER;

ADULT; ANTIVIRAL THERAPY; ARTICLE; CD4+ T LYMPHOCYTE; CELL EXPANSION; CELLULAR IMMUNITY; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOKINE RELEASE; DISEASE COURSE; DISEASE DURATION; EX VIVO STUDY; FEMALE; HEPATITIS C; HUMAN; HUMAN CELL; IN VITRO STUDY; LYMPHOCYTE PROLIFERATION; MALE; NONHUMAN; NUCLEOTIDE SEQUENCE; OUTCOME ASSESSMENT; PERSISTENT VIRUS INFECTION; PRIORITY JOURNAL; VIREMIA; VIRUS IMMUNITY;

ADULT; ANTIBODIES, NEUTRALIZING; ANTIVIRAL AGENTS; CD4-POSITIVE T-LYMPHOCYTES; CELL PROLIFERATION; COHORT STUDIES; EPITOPES, T-LYMPHOCYTE; FEMALE; HEPACIVIRUS; HEPATITIS C; HISTOCOMPATIBILITY ANTIGENS CLASS II; HUMANS; INTERLEUKIN-2; LYMPHOCYTE ACTIVATION; MALE; MIDDLE AGED; REMISSION, SPONTANEOUS; VIREMIA; YOUNG ADULT;

EID: 84856846467     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20100388     Document Type: Article

References (66)

1. Alter, H.J., and L.B. Seeff. 2000. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin. Liver Dis. 20:17-35. http://dx.doi.org/10.1055/s-2000-9505
2. Badr, G., N. Bédard, M.S. Abdel-Hakeem, L. Trautmann, B. Willems, J.P. Villeneuve, E.K. Haddad, R.P. Sékaly, J. Bruneau, and N.H. Shoukry. 2008. Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells. J. Virol. 82:10017-10031. http://dx.doi.org/10.1128/JVI.01083-08
3. Barnes, E., H.C. Gelderblom, I. Humphreys, N. Semmo, H.W. Reesink, M.G. Beld, R.A. van Lier, and P. Klenerman. 2009. Cellular immune responses during high-dose interferon-alpha induction therapy for hepatitis C virus infection. J. Infect. Dis. 199:819-828. http://dx.doi.org/10.1086/597072
4. Bunce, M., C.M. O'Neill, M.C. Barnardo, P. Krausa, M.J. Browning, P.J. Morris, and K.I. Welsh. 1995. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCRSSP). Tissue Antigens. 46:355.
5. Chang, K.M. 2007. Regulatory T cells in hepatitis C virus infection. Hepatol. Res. 37:S327-S330. http://dx.doi.org/10.1111/j.1872-034X.2007.00220.x
6. Chang, K.M., R. Thimme, J.J. Melpolder, D. Oldach, J. Pemberton, J. Moorhead-Loudis, J.G. McHutchison, H.J. Alter, and F.V. Chisari. 2001. Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection. Hepatology. 33:267-276. http://dx.doi.org/10.1053/jhep.2001.21162
7. Corey, K.E., A.S. Ross, A. Wurcel, J. Schulze Zur Wiesch, A.Y. Kim, G.M. Lauer, and R.T. Chung. 2006. Outcomes and treatment of acute hepatitis C virus infection in a United States population. Clin. Gastroenterol. Hepatol. 4:1278-1282. http://dx.doi.org/10.1016/j.cgh.2006.06.026
8. Cox, A.L., T. Mosbruger, G.M. Lauer, D. Pardoll, D.L. Thomas, and S.C. Ray. 2005a. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology. 42:104-112. http://dx.doi.org/10.1002/hep.20749
9. Cox, A.L., T. Mosbruger, Q. Mao, Z. Liu, X.H. Wang, H.C. Yang, J. Sidney, A. Sette, D. Pardoll, D.L. Thomas, and S.C. Ray. 2005b. Cellular immune selection with hepatitis C virus persistence in humans. J. Exp. Med. 201:1741-1752. http://dx.doi.org/10.1084/jem.20050121
10. Cox, A.L., K. Page, J. Bruneau, N.H. Shoukry, G.M. Lauer, A.Y. Kim, H.R. Rosen, H. Radziewicz, A. Grakoui, D.S. Fierer, et al. 2009. Rare birds in North America: acute hepatitis C cohorts. Gastroenterology. 136:26-31. http://dx.doi.org/10.1053/j.gastro.2008.11.049
11. Day, C.L., G.M. Lauer, G.K. Robbins, B. McGovern, A.G. Wurcel, R.T. Gandhi, R.T. Chung, and B.D. Walker. 2002. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J. Virol. 76:12584-12595. http://dx.doi.org/10.1128/JVI.76.24.12584-12595.2002
12. Day, C.L., N.P. Seth, M. Lucas, H. Appel, L. Gauthier, G.M. Lauer, G.K. Robbins, Z.M. Szczepiorkowski, D.R. Casson, R.T. Chung, et al. 2003. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J. Clin. Invest. 112:831-842.
13. Day, C.L., D.E. Kaufmann, P. Kiepiela, J.A. Brown, E.S. Moodley, S. Reddy, E.W. Mackey, J.D. Miller, A.J. Leslie, C. DePierres, et al. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 443:350-354. http://dx.doi.org/10.1038/nature05115
14. Diepolder, H.M. 2009. New insights into the immunopathogenesis of chronic hepatitis C. Antiviral Res. 82:103-109. http://dx.doi.org/10.1016/j.antiviral.2009.02.203
15. Diepolder, H.M., R. Zachoval, R.M. Hoffmann, E.A. Wierenga, T. Santantonio, M.C. Jung, D. Eichenlaub, and G.R. Pape. 1995. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet. 346:1006-1007. http://dx.doi.org/10.1016/S0140-6736(95)91691-1
16. Diepolder, H.M., R. Zachoval, R.M. Hoffmann, M.C. Jung, T. Gerlach, and G.R. Pape. 1996. The role of hepatitis C virus specific CD4+ T lymphocytes in acute and chronic hepatitis C. J. Mol. Med. 74:583-588. http://dx.doi.org/10.1007/s001090050062
17. Diepolder, H.M., J.T. Gerlach, R. Zachoval, R.M. Hoffmann, M.C. Jung, E.A. Wierenga, S. Scholz, T. Santantonio, M. Houghton, S. Southwood, et al. 1997. Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection. J. Virol. 71:6011-6019.
18. Folgori, A., E. Spada, M. Pezzanera, L. Ruggeri, A. Mele, A.R. Garbuglia, M.P. Perrone, P. Del Porto, E. Piccolella, R. Cortese, et al; Acute Hepatitis C Italian Study Group. 2006. Early impairment of hepatitis C virus specific T cell proliferation during acute infection leads to failure of viral clearance. Gut. 55:1012-1019. http://dx.doi.org/10.1136/gut.2005.080077
19. Fuller, M.J., N.H. Shoukry, T. Gushima, D.G. Bowen, B. Callendret, K.J. Campbell, D.L. Hasselschwert, A.L. Hughes, and C.M. Walker. 2010. Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection. Hepatology. 51:378-387. http://dx.doi.org/10.1002/hep.23319
20. Gerlach, J.T., H.M. Diepolder, M.C. Jung, N.H. Gruener, W.W. Schraut, R. Zachoval, R. Hoffmann, C.A. Schirren, T. Santantonio, and G.R. Pape. 1999. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology. 117:933-941. http://dx.doi.org/10.1016/S0016-5085(99)70353-7
21. Gerlach, J.T., A. Ulsenheimer, N.H. Grüner, M.C. Jung, W. Schraut, C.A. Schirren, M. Heeg, S. Scholz, K. Witter, R. Zahn, et al. 2005. Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins. J. Virol. 79:12425-12433. http://dx.doi.org/10.1128/JVI.79.19.12425-12433.2005
22. Golden-Mason, L., B.E. Palmer, N. Kassam, L. Townshend-Bulson, S. Livingston, B.J. McMahon, N. Castelblanco, V. Kuchroo, D.R. Gretch, and H.R. Rosen. 2009. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J. Virol. 83:9122-9130. http://dx.doi.org/10.1128/JVI.00639-09
23. Grakoui, A., N.H. Shoukry, D.J. Woollard, J.H. Han, H.L. Hanson, J. Ghrayeb, K.K. Murthy, C.M. Rice, and C.M. Walker. 2003. HCV persistence and immune evasion in the absence of memory T cell help. Science. 302:659-662. http://dx.doi.org/10.1126/science.1088774
24. Iyasere, C., J.C. Tilton, A.J. Johnson, S. Younes, B. Yassine-Diab, R.P. Sekaly, W.W. Kwok, S.A. Migueles, A.C. Laborico, W.L. Shupert, et al. 2003. Diminished proliferation of human immunodeficiency virusspecific CD4+ T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2. J. Virol. 77:10900-10909. http://dx.doi.org/10.1128/JVI.77.20.10900-10909.2003
25. Kamal, S.M., A. Ismail, C.S. Graham, Q. He, J.W. Rasenack, T. Peters, A.A. Tawil, J.J. Fehr, Kel.S. Khalifa, M.M. Madwar, and M.J. Koziel. 2004. Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology. 39:1721-1731. http://dx.doi.org/10.1002/hep.20266
26. Kaplan, D.E., K. Sugimoto, K. Newton, M.E. Valiga, F. Ikeda, A. Aytaman, F.A. Nunes, M.R. Lucey, B.A. Vance, R.H. Vonderheide, et al. 2007. Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C. Gastroenterology. 132:654-666. http://dx.doi.org/10.1053/j.gastro.2006.11.044
27. Kasprowicz, V., J. Schulze Zur Wiesch, T. Kuntzen, B.E. Nolan, S. Longworth, A. Berical, J. Blum, C. McMahon, L.L. Reyor, N. Elias, et al. 2008. High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J. Virol. 82:3154-3160. http://dx.doi.org/10.1128/JVI.02474-07
28. Kasprowicz, V., Y.H. Kang, M. Lucas, J. Schulze zur Wiesch, T. Kuntzen, V. Fleming, B.E. Nolan, S. Longworth, A. Berical, B. Bengsch, et al. 2010. Hepatitis C virus (HCV) sequence variation induces an HCVspecific T-cell phenotype analogous to spontaneous resolution. J. Virol. 84:1656-1663. http://dx.doi.org/10.1128/JVI.01499-09
29. Klenerman, P., and A. Hill. 2005. T cells and viral persistence: lessons from diverse infections. Nat. Immunol. 6:873-879. http://dx.doi.org/10.1038/ni1241
30. Lauer, G.M., and B.D. Walker. 2001. Hepatitis C virus infection. N. Engl. J. Med. 345:41-52. http://dx.doi.org/10.1056/NEJM200107053450107
31. Lauer, G.M., T.N. Nguyen, C.L. Day, G.K. Robbins, T. Flynn, K. McGowan, E.S. Rosenberg, M. Lucas, P. Klenerman, R.T. Chung, and B.D. Walker. 2002. Human immunodeficiency virus type 1-hepatitis C virus coinfection: intraindividual comparison of cellular immune responses against two persistent viruses. J. Virol. 76:2817-2826. http://dx.doi.org/10.1128/JVI.76.6.2817-2826.2002
32. Lauer, G.M., E. Barnes, M. Lucas, J. Timm, K. Ouchi, A.Y. Kim, C.L. Day, G.K. Robbins, D.R. Casson, M. Reiser, et al. 2004. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology. 127:924-936. http://dx.doi.org/10.1053/j.gastro.2004.06.015
33. Lauer, G.M., M. Lucas, J. Timm, K. Ouchi, A.Y. Kim, C.L. Day, J. Schulze Zur Wiesch, G. Paranhos-Baccala, I. Sheridan, D.R. Casson, et al. 2005. Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy. J. Virol. 79:12979-12988. http://dx.doi.org/10.1128/JVI.79.20.12979-12988.2005
34. Lichterfeld, M., D.E. Kaufmann, X.G. Yu, S.K. Mui, M.M. Addo, M.N. Johnston, D. Cohen, G.K. Robbins, E. Pae, G. Alter, et al. 2004. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J. Exp. Med. 200:701-712. http://dx.doi.org/10.1084/jem.20041270
35. Lucas, M., A.L. Vargas-Cuero, G.M. Lauer, E. Barnes, C.B. Willberg, N. Semmo, B.D. Walker, R. Phillips, and P. Klenerman. 2004. Pervasive influence of hepatitis C virus on the phenotype of antiviral CD8+ T cells. J. Immunol. 172:1744-1753.
36. Lucas, M., A. Ulsenheimer, K. Pfafferot, M.H. Heeg, S. Gaudieri, N. Grüner, A. Rauch, J.T. Gerlach, M.C. Jung, R. Zachoval, et al. 2007. Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection. PLoS One. 2:e649.
37. McGovern, B.H., A. Wurcel, A.Y. Kim, J. Schulze zur Wiesch, I. Bica, M.T. Zaman, J. Timm, B.D. Walker, and G.M. Lauer. 2006. Acute hepatitis C virus infection in incarcerated injection drug users. Clin. Infect. Dis. 42:1663-1670. http://dx.doi.org/10.1086/504327
38. McGovern, B.H., C.E. Birch, M.J. Bowen, L.L. Reyor, E.H. Nagami, R.T. Chung, and A.Y. Kim. 2009. Improving the diagnosis of acute hepatitis C virus infection with expanded viral load criteria. Clinical infectious diseases. 49:1051-1060.
39. Minutello, M.A., P. Pileri, D. Unutmaz, S. Censini, G. Kuo, M. Houghton, M.R. Brunetto, F. Bonino, and S. Abrignani. 1993. Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. J. Exp. Med. 178:17-25. http://dx.doi.org/10.1084/jem.178.1.17
40. Missale, G., R. Bertoni, V. Lamonaca, A. Valli, M. Massari, C. Mori, M.G. Rumi, M. Houghton, F. Fiaccadori, and C. Ferrari. 1996. Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J. Clin. Invest. 98:706-714. http://dx.doi.org/10.1172/JCI118842
41. Nakamoto, N., H. Cho, A. Shaked, K. Olthoff, M.E. Valiga, M. Kaminski, E. Gostick, D.A. Price, G.J. Freeman, E.J. Wherry, and K.M. Chang. 2009. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5:e1000313. http://dx.doi.org/10.1371/journal.ppat.1000313
42. Nelson, D.R., C.G. Marousis, T. Ohno, G.L. Davis, and J.Y. Lau. 1998. Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C. Hepatology. 28:225-230. http://dx.doi.org/10.1002/hep.510280129
43. Neumann-Haefelin, C., J. Timm, H.C. Spangenberg, N. Wischniowski, N. Nazarova, N. Kersting, M. Roggendorf, T.M. Allen, H.E. Blum, and R. Thimme. 2008. Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection. Hepatology. 47:1824-1836. http://dx.doi.org/10.1002/hep.22242
44. Penna, A., G. Missale, V. Lamonaca, M. Pilli, C. Mori, P. Zanelli, A. Cavalli, G. Elia, and C. Ferrari. 2002. Intrahepatic and circulating HLA class II-restricted, hepatitis C virus-specific T cells: functional characterization in patients with chronic hepatitis C. Hepatology. 35:1225-1236. http://dx.doi.org/10.1053/jhep.2002.33153
45. Rahman, F., T. Heller, Y. Sobao, E. Mizukoshi, M. Nascimbeni, H. Alter, S. Herrine, J. Hoofnagle, T.J. Liang, and B. Rehermann. 2004. Effects of antiviral therapy on the cellular immune response in acute hepatitis C. Hepatology. 40:87-97. http://dx.doi.org/10.1002/hep.20253
46. Rehermann, B. 2009. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J. Clin. Invest. 119:1745-1754. http://dx.doi.org/10.1172/JCI39133
47. Rosen, H.R., C. Miner, A.W. Sasaki, D.M. Lewinsohn, A.J. Conrad, A. Bakke, H.G. Bouwer, and D.J. Hinrichs. 2002. Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: correlation with clinical disease stages. Hepatology. 35:190-198. http://dx.doi.org/10.1053/jhep.2002.30293
48. Rosenberg, E.S., J.M. Billingsley, A.M. Caliendo, S.L. Boswell, P.E. Sax, S.A. Kalams, and B.D. Walker. 1997. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 278:1447-1450. http://dx.doi.org/10.1126/science.278.5342.1447
49. Schulze zur Wiesch, J., G.M. Lauer, C.L. Day, A.Y. Kim, K. Ouchi, J.E. Duncan, A.G. Wurcel, J. Timm, A.M. Jones, B. Mothe, et al. 2005. Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. J. Immunol. 175:3603-3613.
50. Schulze Zur Wiesch, J., G.M. Lauer, J. Timm, T. Kuntzen, M. Neukamm, A. Berical, A.M. Jones, B.E. Nolan, S.A. Longworth, V. Kasprowicz, et al. 2007. Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non-genotype 1 infection. Blood. 110:1559-1569. http://dx.doi.org/10.1182/blood-2007-01-069583
51. Schulze Zur Wiesch, J., D. Pieper, I. Stahmer, T. Eiermann, P. Buggisch, A. Lohse, J. Hauber, and J. van Lunzen. 2009. Sustained virological response after early antiviral treatment of acute hepatitis C virus and HIV coinfection. Clin. Infect. Dis. 49:466-472. http://dx.doi.org/10.1086/600399
52. Semmo, N., and P. Klenerman. 2007. CD4+ T cell responses in hepatitis C virus infection. World J. Gastroenterol. 13:4831-4838.
53. Semmo, N., C.L. Day, S.M. Ward, M. Lucas, G. Harcourt, A. Loughry, and P. Klenerman. 2005. Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection. Hepatology. 41:1019-1028. http://dx.doi.org/10.1002/hep.20669
54. Shoukry, N.H., A.G. Cawthon, and C.M. Walker. 2004. Cell-mediated immunity and the outcome of hepatitis C virus infection. Annu. Rev. Microbiol. 58:391-424. http://dx.doi.org/10.1146/annurev.micro.58.030603.123836
55. Smyk-Pearson, S., I.A. Tester, D. Lezotte, A.W. Sasaki, D.M. Lewinsohn, and H.R. Rosen. 2006. Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: implications for vaccine design. J. Infect. Dis. 194:454-463. http://dx.doi.org/10.1086/505714
56. Smyk-Pearson, S., I.A. Tester, J. Klarquist, B.E. Palmer, J.M. Pawlotsky, L. Golden-Mason, and H.R. Rosen. 2008. Spontaneous recovery in acute human hepatitis C virus infection: functional T-cell thresholds and relative importance of CD4 help. J. Virol. 82:1827-1837. http://dx.doi.org/10.1128/JVI.01581-07
57. Spangenberg, H.C., S. Viazov, N. Kersting, C. Neumann-Haefelin, D. McKinney, M. Roggendorf, F. von Weizsäcker, H.E. Blum, and R. Thimme. 2005. Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection. Hepatology. 42:828-837. http://dx.doi.org/10.1002/hep.20856
58. Takaki, A., M. Wiese, G. Maertens, E. Depla, U. Seifert, A. Liebetrau, J.L. Miller, M.P. Manns, and B. Rehermann. 2000. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat. Med. 6:578-582. http://dx.doi.org/10.1038/75063
59. Tester, I., S. Smyk-Pearson, P. Wang, A. Wertheimer, E. Yao, D.M. Lewinsohn, J.E. Tavis, and H.R. Rosen. 2005. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J. Exp. Med. 201:1725-1731. http://dx.doi.org/10.1084/jem.20042284
60. Thimme, R., D. Oldach, K.M. Chang, C. Steiger, S.C. Ray, and F.V. Chisari. 2001. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194:1395-1406. http://dx.doi.org/10.1084/jem.194.10.1395
61. Timm, J., G.M. Lauer, D.G. Kavanagh, I. Sheridan, A.Y. Kim, M. Lucas, T. Pillay, K. Ouchi, L.L. Reyor, J. Schulze zur Wiesch, et al. 2004. CD8 epitope escape and reversion in acute HCV infection. J. Exp. Med. 200:1593-1604. http://dx.doi.org/10.1084/jem.20041006
62. Ulsenheimer, A., M. Lucas, N.P. Seth, J. Tilman Gerlach, N.H. Gruener, A. Loughry, G.R. Pape, K.W. Wucherpfennig, H.M. Diepolder, and P. Klenerman. 2006. Transient immunological control during acute hepatitis C virus infection: ex vivo analysis of helper T-cell responses. J. Viral Hepat. 13:708-714. http://dx.doi.org/10.1111/j.1365-2893.2006.00747.x
63. Urbani, S., B. Amadei, P. Fisicaro, D. Tola, A. Orlandini, L. Sacchelli, C. Mori, G. Missale, and C. Ferrari. 2006. Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses. Hepatology. 44:126-139. http://dx.doi.org/10.1002/hep.21242
64. Urbani, S., B. Amadei, D. Tola, G. Pedrazzi, L. Sacchelli, M.C. Cavallo, A. Orlandini, G. Missale, and C. Ferrari. 2008. Restoration of HCVspecific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment. J. Hepatol. 48:548-558. http://dx.doi.org/10.1016/j.jhep.2007.12.014
65. Wertheimer, A.M., C. Miner, D.M. Lewinsohn, A.W. Sasaki, E. Kaufman, and H.R. Rosen. 2003. Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection. Hepatology. 37:577-589. http://dx.doi.org/10.1053/jhep.2003.50115
66. Wong, D.K., D.D. Dudley, N.H. Afdhal, J. Dienstag, C.M. Rice, L. Wang, M. Houghton, B.D. Walker, and M.J. Koziel. 1998. Liverderived CTL in hepatitis C virus infection: breadth and specificity of responses in a cohort of persons with chronic infection. J. Immunol. 160:1479-1488.