Background. Chronic hepatitis C virus (HCV) infection is characterized by reduced numbers of functional HCV-specific T cells. In addition, chronically HCV-infected individuals have reduced response to vaccine. Alterations in naive CD4 T cell phenotype or function may contribute to these immune impairments.

Methods. Using flow cytometric analysis and enzyme-linked immunospot assay, we examined peripheral naive CD4 T cell phenotype and function in chronically HCV-infected patients and control subjects.

Results. We observed significantly lower absolute cell numbers of naive CD4 T cells in HCV-infected patients, localized to the CD127⁺CD25^low/- and CD31⁺ (RTE) subsets. Moreover, we found greater percentages of naive cells expressing CD25 and KI67 in HCV-infected patients, consistent with immune activation, further supported by higher plasma sCD27 levels. Functional analysis revealed an intact interferon-γ response to allogeneic B cell stimulus. However, after direct TCR stimulation, naive CD4 T cells from HCV-infected patients had altered up-regulation of KI67 and CD25 and less CD27 expression. The latter was associated with elevated baseline activation state. In addition, naive CD4 T cells from HCV-infected patients were more susceptible to cell death.

Conclusions. These numerical and functional defects may contribute to inadequate formation of virus and neoantigen-specific T cell responses during chronic HCV infection.