Chronic Infections with Hepatotropic Viruses: Mechanisms of Impairment of Cellular Immune Responses

ABSTRACT

Chronic hepatitis B and C cause significant morbidity and mortality worldwide. Antiviral therapy suppresses but does not eliminate chronic hepatitis B virus (HBV) infection, and it is effective in only half of all hepatitis C virus (HCV)-infected patients. Because adaptive immune responses are associated with spontaneous resolution of acute HBV and HCV infection, therapeutic enhancement of immune responses has been proposed as alternative or supplementary therapy for chronic infection. However, all efforts have been hampered by poor proliferation and effector functions of HBV- and HCV-specific CD4 and CD8 T cells, which are thought to be due to T cell exhaustion, high antigenic load, and viral escape. Recent studies revealed that endogenous factors, such as regulatory T cells, immunosuppressive cytokines, and inhibitory receptors, also contribute to the impairment of virus-specific T cell responses in chronic infection, perhaps reflecting the host's attempt to protect itself against immune-mediated pathology. These endogenous mechanisms and potential avenues to revert them are the subject of this review.

KEYWORDS

HBV - HCV - T cell - infection - virus - liver

REFERENCES

• 1 Ganem D, Schneider R J. Hepadnaviridae: the viruses and their replication. In: Knipe D, Howley P, Griffin D, Lamb R, Martin M, Roizman B, Straus S Fields Virology. Vol. 2. Philadelphia; Lippincott Williams & Wilkins 2001: 2923-2969
• 2 Lindenbach B D, Rice C M. Flaviviridae: the viruses and their replication. In: Knipe D, Howley P, Griffin D, Lamb R, Martin M, Roizman B, Straus S Fields Virology. Vol. 1. 4th ed. Philadelphia; Lippincott Williams & Wilkins 2001: 991-1041
• 3 Fattovich G. Natural history and prognosis of hepatitis B.  Semin Liver Dis. 2003;  23 47-58
• 4 Hoofnagle J H. Course and outcome of hepatitis C.  Hepatology. 2002;  36 S21-S29
• 5 Lauer G M, Walker B D. Hepatitis C virus infection.  N Engl J Med. 2001;  345 41-52
• 6 Chisari F V, Ferrari C. Hepatitis B virus immunopathogenesis. In: Paul WE Annual Review of Immunology. 13th ed. Palo Alto; Annual Reviews Inc 1995: 29-60
• 7 Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.  Nat Rev Immunol. 2005;  5 215-229
• 8 Gale Jr M, Foy E M. Evasion of intracellular host defence by hepatitis C virus.  Nature. 2005;  436 939-945
• 9 Shoukry N H, Grakoui A, Houghton M et al.. Memory CD8 + T cells are required for protection from persistent hepatitis C virus infection.  J Exp Med. 2003;  197 1645-1655
• 10 Diepolder H M, Zachoval R, Hoffmann R M et al.. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.  Lancet. 1995;  346 1006-1007
• 11 Lechner F, Wong D K, Dunbar P R et al.. Analysis of successful immune responses in persons infected with hepatitis C virus.  J Exp Med. 2000;  191 1499-1512
• 12 Missale G, Bertoni R, Lamonaca V et al.. 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. 1996;  98 706-714
• 13 Cox A L, Mosbruger T, Lauer G M et al.. Comprehensive analyses of CD8 + T cell responses during longitudinal study of acute human hepatitis C.  Hepatology. 2005;  42 104-112
• 14 Thimme R, Oldach D, Chang K M et al.. Determinants of viral clearance and persistence during acute hepatitis C virus infection.  J Exp Med. 2001;  194 1395-1406
• 15 Thimme R, Bukh J, Spangenberg H C et al.. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease.  Proc Natl Acad Sci USA. 2002;  99 15661-15668
• 16 Rehermann B, Ferrari C, Pasquinelli C et al.. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response.  Nat Med. 1996;  2 1104-1108
• 17 Takaki A, Wiese M, Maertens G et al.. Cellular immune responses persist, humoral responses decrease two decades after recovery from a single source outbreak of hepatitis C.  Nat Med. 2000;  6 578-582
• 18 Thimme R, Wieland S, Steiger C et al.. CD8( + ) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.  J Virol. 2003;  77 68-76
• 19 Grakoui A, Shoukry N H, Woollard D J et al.. HCV persistence and immune evasion in the absence of memory T cell help.  Science. 2003;  302 659-662
• 20 Ferrari C, Penna A, Bertoletti A et al.. Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection.  J Immunol. 1990;  145 3442-3449
• 21 Rehermann B, Fowler P, Sidney J et al.. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.  J Exp Med. 1995;  181 1047-1058
• 22 Wedemeyer H, He X-S, Nascimbeni M et al.. Impaired effector function of hepatitis C virus-specific CD8 + T cells in chronic hepatitis C virus infection.  J Immunol. 2002;  169 3447-3458
• 23 Wherry E J, Blattman J N, Murali-Krishna K et al.. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.  J Virol. 2003;  77 4911-4927
• 24 Milich D R, Jones J E, Hughes J L et al.. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero'.  Proc Natl Acad Sci U S A. 1990;  87 6599-6603
• 25 Reignat S, Webster G J, Brown D et al.. Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection.  J Exp Med. 2002;  195 1089-1101
• 26 Kittlesen D J, Chianese-Bullock K A, Yao Z Q et al.. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation.  J Clin Invest. 2000;  106 1239-1249
• 27 Large M K, Kittlesen D J, Hahn Y S. Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence.  J Immunol. 1999;  162 931-938
• 28 Eisen-Vandervelde A L, Waggoner S N, Yao Z Q et al.. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation.  J Biol Chem. 2004;  279 43479-43486
• 29 Zajac A J, Blattman J N, Murali-Krishna K et al.. Viral immune evasion due to persistence of activated T cells without effector function.  J Exp Med. 1998;  188 2205-2213
• 30 Seifert U, Liermann H, Racanelli V et al.. Hepatitis C virus mutation affects proteasomal epitope processing.  J Clin Invest. 2004;  114 250-259
• 31 Kimura Y, Gushima T, Rawale S et al.. Escape mutations alter proteasome processing of major histocompatibility complex class I-restricted epitopes in persistent hepatitis C virus infection.  J Virol. 2005;  79 4870-4876
• 32 Chang K M, Rehermann B, McHutchison J G et al.. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus.  J Clin Invest. 1997;  100 2376-2385
• 33 Tsai S L, Chen Y M, Chen M H et al.. Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity.  Gastroenterology. 1998;  115 954-965
• 34 Shimizu Y K, Hijikita M, Iwamoto A et al.. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses.  J Virol. 1994;  68 1494-1500
• 35 Farci P, Shimoda A, Coiana A et al.. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies.  Science. 2000;  288 339-344
• 36 Cooper S, Erickson A L, Adams E J et al.. Analysis of a successful immune response against hepatitis C virus.  Immunity. 1999;  10 439-449
• 37 Erickson A L, Kimura Y, Igarashi S et al.. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes.  Immunity. 2001;  15 883-895
• 38 Rehermann B, Pasquinelli C, Mosier S M et al.. Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection.  J Clin Invest. 1995;  96 1527-1534
• 39 Bertoletti A, Sette A, Chisari F V et al.. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells.  Nature. 1994;  369 407-410
• 40 Bertoletti A, Constanzo A, Chisari F V et al.. Cytotoxic T lymphocyte response to a wild-type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope.  J Exp Med. 1994;  180 933-943
• 41 Kemball C C, Lee E D, Vezys V et al.. Late priming and variability of epitope-specific CD8 + T cell responses during a persistent virus infection.  J Immunol. 2005;  174 7950-7960
• 42 Zajac A J, Murali-Krishna K, Blattman J N et al.. Therapeutic vaccination against chronic viral infection: the importance of cooperation between CD4 + and CD8 + T cells.  Curr Opin Immunol. 1998;  10 444-449
• 43 Fuller M J, Zajac A J. Ablation of CD8 and CD4 T cell responses by high viral loads.  J Immunol. 2003;  170 477-486
• 44 van der Most R G, Murali-Krishna K, Lanier J G et al.. Changing immunodominance patterns in antiviral CD8 T-cell responses after loss of epitope presentation or chronic antigenic stimulation.  Virology. 2003;  315 93-102
• 45 Gruener N H, Lechner F, Jung M C et al.. Sustained dysfunction of antiviral CD8 + T lymphocytes after infection with hepatitis C virus.  J Virol. 2001;  75 5550-5558
• 46 Vezys V, Masopust D, Kemball C C et al.. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection.  J Exp Med. 2006;  203 2263-2269
• 47 Tsai S L, Chen M Y, Lai M Y et al.. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens.  J Clin Invest. 1992;  89 87-96
• 48 Heathcote J, McHutchison J, Lee S et al.. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group.  Hepatology. 1999;  30 531-536
• 49 Dikici B, Kalayci A G, Ozgenc F et al.. Therapeutic vaccination in the immunotolerant phase of children with chronic hepatitis B infection.  Pediatr Infect Dis J. 2003;  22 345-349
• 50 Hel Z, Venzon D, Poudyal M et al.. Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques.  Nat Med. 2000;  6 1140-1146
• 51 Wherry E J, Blattman J N, Ahmed R. Low CD8 T-cell proliferative potential and high viral load limit the effectiveness of therapeutic vaccination.  J Virol. 2005;  79 8960-8968
• 52 Pancholi P, Lee D H, Liu Q et al.. DNA prime/canarypox boost-based immunotherapy of chronic hepatitis B virus infection in a chimpanzee.  Hepatology. 2001;  33 448-454
• 53 Shata M T, Pfahler W, Brotman B et al.. Attempted therapeutic immunization in a chimpanzee chronic HBV carrier with a high viral load.  J Med Primatol. 2006;  35 165-171
• 54 Boni C, Bertoletti A, Penna A et al.. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.  J Clin Invest. 1998;  102 968-975
• 55 Boni C, Penna A, Ogg G S et al.. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy.  Hepatology. 2001;  33 963-971
• 56 Boni C, Penna A, Bertoletti A et al.. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B.  J Hepatol. 2003;  39 595-605
• 57 Mizukoshi E, Sidney J, Livingston B et al.. Cellular immune responses to the hepatitis B virus polymerase.  J Immunol. 2004;  173 5863-5871
• 58 Tester I, Smyk-Pearson S, Wang P et al.. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source.  J Exp Med. 2005;  201 1725-1731
• 59 Lauer G M, Lucas M, Timm J et al.. Full-breadth analysis of CD8 + T-cell responses in acute hepatitis C virus infection and early therapy.  J Virol. 2005;  79 12979-12988
• 60 Rahman F, Heller T, Sobao Y et al.. Effects of antiviral therapy on the cellular immune response in acute hepatitis C.  Hepatology. 2004;  40 87-97
• 61 Boni C, Amadei B, Urbani S et al.. Antiviral CD8-mediated responses in chronic HCV carriers with HBV superinfection.  Hepatology. 2004;  40 289-299
• 62 Ishida Y, Agata Y, Shibahara K et al.. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.  EMBO J. 1992;  11 3887-3895
• 63 Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity.  Nat Rev Immunol. 2004;  4 336-347
• 64 Greenwald R J, Freeman G J, Sharpe A H. The B7 family revisited.  Annu Rev Immunol. 2005;  23 515-548
• 65 Iwai Y, Terawaki S, Ikegawa M et al.. PD-1 inhibits antiviral immunity at the effector phase in the liver.  J Exp Med. 2003;  198 39-50
• 66 Chen C H, Kuo L M, Chang Y et al.. In vivo immune modulatory activity of hepatic stellate cells in mice.  Hepatology. 2006;  44 1171-1181
• 67 Muhlbauer M, Fleck M, Schutz C et al.. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis.  J Hepatol. 2006;  45 520-528
• 68 Dong H, Zhu G, Tamada K et al.. B7-H1 determines accumulation and deletion of intrahepatic CD8( + ) T lymphocytes.  Immunity. 2004;  20 327-336
• 69 Isogawa M, Furuichi Y, Chisari F V. Oscillating CD8( + ) T cell effector functions after antigen recognition in the liver.  Immunity. 2005;  23 53-63
• 70 Barber D L, Wherry E J, Masopust D et al.. Restoring function in exhausted CD8 T cells during chronic viral infection.  Nature. 2006;  439 682-687
• 71 Urbani S, Amadei B, Tolo D et al.. PD-1 expression in acute hepatitis C is associated with HCV-specific CD8 exhaustion.  J Virol. 2006;  80 11398-11403
• 72 Radziewicz H, Ibegbu C C, Fernandez M L et al.. Liver infiltrating lymphocytes in chronic human HCV infection display an exhausted phenotype with high PD-1 and low CD127 expression.  J Virol. 2007;  81 2545-2553
• 73 Geng L, Jiang G, Fang Y et al.. B7-H1 expression is upregulated in peripheral blood CD14 + monocytes of patients with chronic hepatitis B virus infection, which correlates with higher serum IL-10 levels.  J Viral Hepat. 2006;  13 725-733
• 74 Accapezzato D, Francavilla V, Paroli M et al.. Hepatic expansion of a virus-specific regulatory CD8( + ) T cell population in chronic hepatitis C virus infection.  J Clin Invest. 2004;  113 963-972
• 75 Dikopoulos N, Bertoletti A, Kroger A et al.. Type I IFN negatively regulates CD8 + T cell responses through IL-10-producing CD4 + T regulatory 1 cells.  J Immunol. 2005;  174 99-109
• 76 Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control.  J Exp Med. 2007;  204 239-243
• 77 Dolganiuc A, Chang S, Kodys K et al.. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection.  J Immunol. 2006;  177 6758-6768
• 78 Duramad O, Fearon K L, Chan J H et al.. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences.  Blood. 2003;  102 4487-4492
• 79 Piazzolla G, Tortorella C, Schiraldi O et al.. Relationship between interferon-gamma, interleukin-10, and interleukin-12 production in chronic hepatitis C and in vitro effects of interferon-alpha.  J Clin Immunol. 2000;  20 54-61
• 80 Jia H Y, Du J, Zhu S H et al.. The roles of serum IL-18, IL-10, TNF-alpha and sIL-2R in patients with chronic hepatitis C.  Hepatobiliary Pancreat Dis Int. 2002;  1 378-382
• 81 Wertheimer A M, Bakke A, Rosen H R. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease.  Hepatology. 2004;  40 335-345
• 82 Longman R S, Talal A H, Jacobson I M et al.. Presence of functional dendritic cells in patients chronically infected with hepatitis C virus.  Blood. 2004;  103 1026-1029
• 83 Jankovic D, Kullberg M C, Feng C G et al.. Conventional T-bet( + )Foxp3(-)Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.  J Exp Med. 2007;  204 273-283
• 84 Anderson C F, Oukka M, Kuchroo V J, Sacks D. CD4( + )CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.  J Exp Med. 2007;  204 285-297
• 85 Abel M, Sene D, Pol S et al.. Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection.  Hepatology. 2006;  44 1607-1616
• 86 Ejrnaes M, Filippi C M, Martinic M M et al.. Resolution of a chronic viral infection after interleukin-10 receptor blockade.  J Exp Med. 2006;  203 2461-2472
• 87 Akiba H, Nakano H, Nishinaka S et al.. CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase.  J Biol Chem. 1998;  273 13353-13358
• 88 Tesselaar K, Arens R, van Schijndel G M et al.. Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions.  Nat Immunol. 2003;  4 49-54
• 89 Matter M, Odermatt B, Yagita H et al.. Elimination of chronic viral infection by blocking CD27 signaling.  J Exp Med. 2006;  203 2145-2155
• 90 Hazenberg M D, Otto S A, van Benthem B H et al.. Persistent immune activation in HIV-1 infection is associated with progression to AIDS.  AIDS. 2003;  17 1881-1888
• 91 De Milito A, Nilsson A, Titanji K et al.. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection.  Blood. 2004;  103 2180-2186
• 92 Sakaguchi S, Sakaguchi N, Asano M et al.. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.  J Immunol. 1995;  155 1151-1164
• 93 Shimizu J, Yamazaki S, Takahashi T et al.. Stimulation of CD25( + )CD4( + ) regulatory T cells through GITR breaks immunological self-tolerance.  Nat Immunol. 2002;  3 135-142
• 94 Shevach E M. CD4 + CD25 + suppressor T cells: more questions than answers.  Nat Rev Immunol. 2002;  2 389-400
• 95 Stoop J N, van der Molen R G, Baan C C et al.. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection.  Hepatology. 2005;  41 771-778
• 96 Xu D, Fu J, Jin L et al.. Circulating and liver resident CD4 + CD25 + regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B.  J Immunol. 2006;  177 739-747
• 97 Sugimoto K, Ikeda F, Stadanlick J et al.. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection.  Hepatology. 2003;  38 1437-1448
• 98 Cabrera R, Tu Z, Xu Y et al.. An immunomodulatory role for CD4( + )CD25( + ) regulatory T lymphocytes in hepatitis C virus infection.  Hepatology. 2004;  40 1062-1071
• 99 Boettler T, Spangenberg H C, Neumann-Haefelin C et al.. T cells with a CD4 + CD25 + regulatory phenotype suppress in vitro proliferation of virus-specific CD8 + T cells during chronic hepatitis C virus infection.  J Virol. 2005;  79 7860-7867
• 100 Rushbrook S M, Ward S M, Unitt E et al.. Regulatory T cells suppress in vitro proliferation of virus-specific CD8 + T cells during persistent hepatitis C virus infection.  J Virol. 2005;  79 7852-7859
• 101 Jordan M S, Boesteanu A, Reed A J et al.. Thymic selection of CD4 + CD25 + regulatory T cells induced by an agonist self-peptide.  Nat Immunol. 2001;  2 301-306
• 102 Bluestone J A, Abbas A K. Natural versus adaptive regulatory T cells.  Nat Rev Immunol. 2003;  3 253-257
• 103 Manigold T, Shin E C, Mizukoshi E et al.. Foxp3 + CD4 + CD25 + T cells control virus-specific memory T cells in chimpanzees recovered from Hepatitis C.  Blood. 2006;  107 4424-4432
• 104 Camara N O, Sebille F, Lechler R I. Human CD4 + CD25 + regulatory cells have marked and sustained effects on CD8 + T cell activation.  Eur J Immunol. 2003;  33 3473-3483
• 105 Piccirillo C A, Shevach E M. Cutting edge: control of CD8 + T cell activation by CD4 + CD25 + immunoregulatory cells.  J Immunol. 2001;  167 1137-1140
• 106 Manigold T, Shin E C, Mizukoshi E et al.. Foxp3 + CD4 + CD25 + T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C.  Blood. 2006;  107 4424-4432
• 107 Sempowski G D, Gooding M E, Liao H X et al.. T cell receptor excision circle assessment of thymopoiesis in aging mice.  Mol Immunol. 2002;  38 841-848
• 108 Dittmer U, He H, Messer R J et al.. Functional impairment of CD8( + ) T cells by regulatory T cells during persistent retroviral infection.  Immunity. 2004;  20 293-303
• 109 Zelinskyy G, Robertson S J, Schimmer S et al.. CD8 + T-cell dysfunction due to cytolytic granule deficiency in persistent Friend retrovirus infection.  J Virol. 2005;  79 10619-10626
• 110 Zelinskyy G, Kraft A R, Schimmer S et al.. Kinetics of CD8 + effector T cell responses and induced CD4 + regulatory T cell responses during Friend retrovirus infection.  Eur J Immunol. 2006;  36 2658-2670