Subinfectious Hepatitis C Virus Exposures Suppress T cell Responses Against Subsequent Acute Infection

Hepatitis C virus (HCV) is endemic in many countries due to its high propensity to establish persistence(1). The presence of HCV–specific T cells in repeatedly HCV–exposed subjects who test for HCV RNA and antibodies and do not have any history of HCV infection has been interpreted as T cell–mediated protection(2-5). Here, we show in nonhuman primates that repeated exposure to human plasma with trace amounts of HCV induced HCV–specific T cells without seroconversion and systemic viremia, but did not protect upon subsequent HCV challenge. Rather, HCV–specific recall and de novo T cell responses as well as intrahepatic T cell recruitment and IFN-γ production were suppressed upon HCV challenge, concomitant to quantitative and qualitative changes in regulatory T (T(reg)) cells that began after subinfectious HCV exposure and increased after HCV challenge. In vitro T(reg) cell depletion restored HCV–specific T cell responses. Thus, T cells primed by trace amounts of HCV do not generate effective recall responses upon subsequent HCV infection. Subinfectious HCV exposure predisposes to T(reg) cell expansion, which suppresses effector T cells during subsequent infection. Strategies to reverse this exposure–induced suppression should be examined to aid the development of T cell–based vaccines against HCV and other endemic pathogens.