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Abstract and Introduction
Abstract
Background 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 CD4count).
Methods We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4and 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
Results 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 D4 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.
Conclusions 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.
Introduction
T cells play an important role in the adaptive immune response to acute hepatitis C virus (HCV) infection. In particular, broad and sustained CD4 and CD8 T-cell responses against HCV antigens after acute infection have been prospectively associated with subsequent immune clearance of HCV viremia. In individuals with chronic HCV infection, however, T-cell responses against HCV antigens are generally weak or even undetected despite ongoing viral replication. Furthermore, a large fraction of HCV-specific CD8 T cells express cell surface markers of differentiation and exhaustion during chronic HCV infection, and these cells are susceptible to apoptosis. However, the broader impact of chronic HCV infection on overall T-cell differentiation and activation, including T cells that are not specific for HCV antigens, is not well understood. These relationships are important because nonspecific immune activation in individuals with chronic HCV infection has been hypothesized to contribute to the development of extrahepatic conditions, including diabetes and cardiovascular disease (CVD) that are found in excess among these individuals.
Three recent studies examined T-cell phenotypes in HCV-viremic individuals and HCV-uninfected controls. All 3 studies reported lower percentages of naive CD4 T cells, and 1 study also reported a lower percentage of naive CD8 T cells in HCV-viremic individuals as compared with HCV-seronegative controls. The data from these studies were not consistent, although, regarding percentages of central memory (CM), effector memory (EM), and terminally differentiated effector (TE) T cells by HCV viremia status. EM and TE cells have shortened telomeres as compared with naive and CM cells and represent more differentiated T-cell phenotypes, with diminished capacity to replicate in response to antigenic stimulation.
Studies by our group and others have additionally examined T-cell expression of activation markers (eg, CD38 and HLA-DR) in HCV-viremic individuals compared with uninfected controls. Most of these studies found no differences in the percentage of CD4 and CD8 T cells that were activated by HCV status, although 1 study found that CD4 T-cell activation was higher in those with HCV viremia. Comparisons of the percentage of regulatory CD4 T cells (Tregs) between individuals with HCV viremia and HCV-uninfected controls have also been conducted, but the data have conflicted.
An important limitation of these previous studies is that the HCV-uninfected controls were often healthy individuals from the general population that differed in important ways from the subjects with HCV viremia. For example, cigarette smoking and injection drug use (IDU) are more common in HCV-seropositive individuals than in the general population and may have a strong influence on the immune response in general and on T-cell function in particular. Finally, although the association of HCV viremia with T-cell differentiation and activation in HIV-positive individuals has been studied, no previous investigation directly tested whether the relation of HCV viremia to T-cell differentiation and activation might differ according to the overall level of immunosuppression as measured by total CD4 T cell count.
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