Background:  Hepatitis C virus (HCV) liver disease progresses more rapidly in HIV-infected individuals, and HCV liver disease is a major cause of morbidity and mortality in the combination ART (cART) era. We hypothesized that HIV-specific T cells accumulate in the liver of HIV/HCV-co-infected individuals, promoting hepatic inflammation through bystander activation. Tumor necrosis factor-alpha (TNF-α) is thought to be a fibrogenic cytokine.

Methods:  Liver biopsies were performed pre-treatment in 6 HCV-mono-infected and 14 HCV/HIV-co-infected individuals. Intra-hepatic lymphocytes ex vivo were stimulated overnight with peptide pools spanning the entire genome of HIV and HCV, and then assessed for interferon gamma (IFN-γ) and (TNF-α) production by intracellular cytokine flow cytometry.

Results:  Similar numbers of lymphocytes were present in HCV versus HCV/HIV biopsies, however, lymphocytes from HCV/HIV had lwwer percentages of CD4 cells (p <0.05). We found similar frequencies of HCV-specific CD4 and CD8 T cells producing IFN-γ and TNF-α in HCV versus HCV/HIV. In HCV/HIV-co-infected individuals we also observed the presence of HIV-specific CD4 and CD8 T cells producing IFN-γ and TNF-α, similar in frequency to those that are HCV specific. In the HCV/HIV biopsies the mean percentage of HIV-specific CD4 cells producing IFN-γ and TNF-α were 7.0% and 11.0% of total CD4, and the mean percentage of HIV-specific CD8 cells producing IFN-γ and TNF-α were 6.0% and 9.0% of total CD8. Comparison of the percentage of total virus specific hepatic T cells (HIV plus HCV) producing the pro-fibrogenic cytokine TNF-α in both cohorts reveals significantly greater frequencies in the co-infected individuals, indicating a more intense inflammatory activity. Of HCV/HIV co-infected, cART was associated with increased total lymphocyte numbers and fibrosis score, a reduced percentage of HIV-specific CD4 (p <0.05), but not HIV-specific CD8, and a decrease in percentage of HCV-specific CD8 producing TNF-α (p <0.05).

Conclusions:  Significant numbers of HIV-specific T cells are deposited in the liver of co-infected individuals, resulting in an increase in intra-hepatic viral-specific TNF-α T-cell responses. This mechanism may explain the faster progression of HCV disease in HCV/HIV-co-infected individuals, and further studies examining the effect of cART on this activity and HCV disease progression are warranted.