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Hepatitis C virus (HCV) viremia is thought to have broad systemic effects on the cellular immune system that go beyond its impact on just those T cells that are HCV specific. However, previous studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV positives did not address overall immune status (total CD4+ count).We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T cells, Tregs, and T-cell differentiation phenotypes (naive, central memory, effector memory (EM), and terminally differentiated effector). This included 158 HIV negatives and 464 HIV positives, of whom 18 and 63, respectively, were HCV viremic.In multivariate models of HIV negatives, HCV viremia was associated with 25% fewer naive CD4+ (P = 0.03), 33% more EM CD4+ (P = 0.0002), and 37% fewer central memory CD8+ (P = 0.02) T cells. Among HIV positives, we observed only 1 of these 3 relationships: higher percentage of EM CD4+ among HCV viremic women. Furthermore, the association with EM CD4+ among HIV positives was limited to individuals with diminished immune status (total CD4+ count ≤500 cells/μL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV positives with high CD4+ count, no significant associations were observed.These data suggest that HCV viremia in HIV negatives is associated with accelerated T-cell differentiation, but among HIV positives, the impact of HCV viremia is less straightforward and varies by total CD4+ count.