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Background: Lymphotropic hepatitis C virus (HCV) infection of B and T cells might play an important role in the pathogenesis of hepatitis C. Recently, we showed that a lymphotropic HCV (SB strain) could infect established T-cell lines and B-cell lines. However, whether HCV replication interferes with cell proliferation and function in primary T lymphocytes is still unclear. Aim: The aim of this study was to analyze whether HCV replication in primary T lymphocytes affected their development, proliferation, and Th1 commitment. Methods: SB strain cell culture supernatant (2 × 10 copies/ml HCV) was used to infect several kinds of primary lymphocyte subsets. Mock, UV-irradiated SB-HCV, JFH-1 strain, and JFH-1 NS5B mutant, which could not replicate in T cells, were included as negative controls. Carboxyfluorescein succinimidyl ester (CFSE) and CD45RA double staining was used to evaluate the proliferative activity of CD4CD45RACD45RO naïve CD4 cells. Interferon (IFN)-γ and interleukin (IL)-10 secretion assays magnetic cell sorting (MACS) were carried out. Results: Negative strand HCV RNA was detected in CD4, CD14, and CD19 cells. Among CD4 cells, CD4CD45RARO cells (naïve CD4 cells) were most susceptible to replication of the SB strain. The levels of CFSE and CD45RA expression gradually declined during cell division in uninfected cells, while HCV-infected naïve CD4 cells expressed higher levels of CFSE and CD45RA than Mock or UV-SB infected naïve CD4 cells. Moreover, the production of IFN-γ was significantly suppressed in SB-infected naïve CD4 cells. Conclusions: Lymphotropic HCV replication suppressed proliferation and development, including that towards Th1 commitment, in human primary naïve CD4 cells. [ABSTRACT FROM AUTHOR]