Background:  Virus-specific CD8⁺ cells play an important role in control of both SIV in macaques and HCV in chimpanzees, but no animal model has adequately studied HIV/HCV co-infection.  We performed cross-sectional analysis in a large cohort of co-infected humans to determine the effects of HIV on HCV-specific functional immunity.

Methods:  We studied 61 HIV⁺/HCV⁺ co-infected and 22 HIV^-/HCV⁺ mono-infected individuals. No subject had ever received interferon therapy for chronic HCV.  To determine comprehensively the HCV-specific CD8⁺ response in peripheral blood, we applied established approaches using a matrix IFN-g ELISpot with 494 peptides that span the entire genome, verifying novel responses by generation of specific T-cell lines and testing by intracellular cytokine staining. HIV-1 responses were determined using analogous comprehensive approaches. Tetramers were then used for further analysis.

Results:  We detected ex vivo HCV-specific CD8 cells in 29/61 (47.5%) of co-infected and in 9/22 (40.9%) of mono-infected individuals. Single tetramer responses were as high as 3.6% of circulating CD8 cells. When analyzing persons with chronic HCV viremia (46 HIV⁺ versus 22 HIV^- subjects), there were no differences in breadth (p = 0.58) or magnitude (p = 0.53) between the mono- and co-infected groups.  However, a significant relationship emerged between peripheral CD4 cell counts and breadth (i>R = 0.44, p <0.001) and magnitude of HCV-specific responses (R = 0.40, p = 0.002).  This relationship was significant whether when analysis was restricted to HAART status and to those with genotype 1.  In contrast, no such correlation existed for HIV-1 responses.  Longitudinal data on subjects followed on HAART and phenotypic data will also be presented.

Conclusions:  Surprisingly high frequencies of HCV-specific CD8 T cells are detected in HIV infection and did not differ from those without HIV.  Only when CD4 cells are depleted due to progressive HIV is the HCV^--specific CD8⁺ response significantly diminished. Conversely, these results suggest that functional immunity specific for HCV may augment on HAART, in contrast to HIV-1 responses which decline.  These results shed insight into the relationship between CD4⁺ and CD8⁺ cells in a human viral infection.  Moreover, these data provide rationale for further detailed longitudinal studies on HAART, to study prospectively immune reconstitution in co-infected subjects.

Keywords: Hepatitis C; CD8+ T lymphocytes; Immunology