Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection

Abstract

BackgroundHepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.Methods and FindingsWe measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r 2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).ConclusionsThese results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.

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.…”

Acceleration of Hepatitis C Virus Envelope Evolution in Humans Is Consistent with Progressive Humoral Immune Selection during the Transition from Acute to Chronic Infection

“…In HCV-infected individuals who progress to chronicity, neutralizing antibody responses do not seem to initiate until the chronic phase is established (12,40), whereas cellular responses are readily detected during the acute phase but lose function during prolonged infection for reasons that are poorly understood (9,10,24,27,44). Across the HCV genome, CD8 T-cell epitopes have been mapped, and all genes seem to be potential targets of cellular immune pressure (9,10,25,49).…”

Hepatitis C Virus Transmission Bottlenecks Analyzed by Deep Sequencing

“…Approximately one-third of HIV-infected patients are coinfected with HCV (35), and HIV coinfection increases HCV-related liver diseases (10), raising the question of how HIV coinfection affects the structure and evolution of HCV populations. One possibility is that immune impairment due to advanced HIV infection results in reduced immune pressure on HCV populations (4,18) and thus in diminished HCV diversity. To investigate this issue, we compared HCV sequence diversities in HIV-HCV-coinfected and HCV-monoinfected patients.…”