The magnitude and breadth of hepatitis C virus–specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1

Abstract

IntroductionHepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) share routes of transmission, are often harbored within the same host, and establish chronic infections characterized by high plasma viral loads. In humans coinfected with HCV and HIV-1, the disease course for HCV infection is accelerated particularly at lower CD4 ϩ counts, with higher HCV viral loads, and more rapid liver fibrosis, although the mechanisms for this differential pathogenicity are unclear. 1,2 HCV has thereby emerged as an important cause of morbidity and mortality in persons infected with HIV-1. Since responses to standard anti-HCV therapy remain suboptimal, particularly for individuals infected with HIV-1, novel approaches such as immunotherapy are needed for this population. 3 Given this need for novel therapies, a better understanding of disease pathogenesis in coinfected persons is of paramount importance.The role of virus-specific immune responses in both HCV infection and HIV-1 infection remains controversial. In both, early containment (HIV-1) or clearance (HCV) of infection is associated with induction of strong CD4 ϩ and CD8 ϩ T-cell responses (reviewed in McMichael and Rowland-Jones 4 and Racanelli and Rehermann 5 ). However, these same responses have been postulated to play a role in disease pathogenesis, due to accelerated destruction of hepatocytes in the case of HCV and lymphocytes in the case of HIV-1. [6][7][8][9][10][11] Some have proposed that the phenomenon of accelerated fibrosis in individuals coinfected with HCV and HIV-1 may be related to loss or dysregulation of these immuneresponses. 12,13 In murine models of persistent viral infection, CD4 ϩ T cells are vital for maintenance of cytotoxic T lymphocyte (CTL) effector functions such as cytokine secretion and secondary expansion upon encounter with antigen, and the development of virus-specific memory responses is impaired in the absence of CD4 ϩ T cells at the time of exposure. 14,15 Moreover, recent depletion experiments in chimpanzees highlight the importance of both CD4 ϩ and CD8 ϩ T cells in control of HCV viremia and illustrate the vital role of CD4 ϩ cells in supporting HCV-specific CTLs. 16,17 Such observations raise the possibility that CD4 ϩ cell depletion that accompanies progressive HIV-1 infection might lead to loss of critical adaptive immune responses to HCV in coinfected persons, and thereby facilitate HCV disease progression.In the present study, we quantified CD8 ϩ T-cell responses to HCV, HIV-1, and Epstein-Barr virus (EBV) to test the hypothesis that CD4 ϩ cell depletion would be associated with impaired virus-specific immune responses. We compared breadth, magnitude, and specificity of HCV-specific CD8 ϩ T-cell responses For personal use only. on April 30, 2019. by guest www.bloodjournal.org From between individuals monoinfected with HCV and individuals coinfected with HCV and HIV-1. Next, we determined the effect of CD4 ϩ T-cell depletion secondary to HIV-1 on the frequency of HCV-specific CD8 ϩ T cells, as measured by e...

Polyfunctional HCV‐specific T‐cell responses are associated with effective control of HCV replication

“…Indeed, 17 CD4 1 and 17 CD8 1 HCV-specific T-cell responses were detected in 34 patients tested. A tendency to a larger proportion of HCV-specific CD8 1 T-cell responses was found in HIV/HCV co-infected patients (10 out of 17), as previously observed [14,15], while a larger proportion of CD4 1 T-cell responses was detected in liver transplant recipients (10 out of 14, Tables 1 and 2). …”

“…These include a lower CD4 1 T-cell counts in co-infected patients [14,15] and the immunosuppressive therapy in liver transplantation. In this regard, it is worth mentioning that CD4 T-cell counts were significantly lower in HIV/HCV co-infected patients as compared with HCV mono-infected patients (Table 3, Po0.001).…”

“…Recent studies investigating the presence of HCV-specific T-cell responses in HIV-1 co-infected individuals have shown that their occurrence was not reduced [13][14][15] but the breadth of the response was limited and they were mostly composed of CD8 1 T cells. Similarly, studies assessing the presence of HCV-specific T-cell responses in liver transplant recipients have shown that these were indeed detectable despite immunosuppression [16][17][18][19][20].…”

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

“…There were 130 (40%) individuals coinfected with human immunodeficiency virus (HIV) in the study, of whom the majority (91% in the Swiss HIV Cohort Study and 75% in the Australian cohort) had a CD4 ϩ T cell count above 200 cells/ L, which others have shown is generally sufficient to maintain HCV-specific CD8 ϩ T cell activity. 16,17 As shown in Supporting Fig. 1, the HLA class I allele frequency distribution was typical of Caucasian populations and was similar across the study groups.…”

“…Second, the inclusion of a substantial proportion (40%) of individuals coinfected with HIV might influence the degree of HLAassociated viral polymorphisms as severe HIV-induced immunosuppression is associated with lower HCV-specific T cell responses. 16,17 However, the large majority (90%) of the coinfected individuals in this study had a CD4 ϩ T cell count above 200 cells/ L. We would therefore expect that the HLA-restricted immune pressure in the coinfected individuals would be similar to that for monoinfected individuals. In addition, HCV infection precedes HIV infection in the large majority of cases.…”