title: Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection.
abstract: Hepatitis C virus (HCV) is endemic in many countries due to its high propensity for establishing persistence. The presence of HCV-specific T cells in subjects repeatedly exposed to HCV who test negative for HCV RNA and antibodies and who do not have any history of HCV infection has been interpreted as T cell-mediated protection. 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 interferon-γ (IFN-γ) production, were suppressed upon HCV challenge, concomitant with quantitative and qualitative changes in regulatory T cells (T(reg) cells) that occurred 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 immune suppression should be examined to aid in the development of T cell-based vaccines against HCV and other endemic pathogens.
authors.affiliation: Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Su-Hyung
authors.initials: SH
authors.lastname: Park
authors.forename: Naga Suresh
authors.initials: NS
authors.lastname: Veerapu
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.forename: Angélique
authors.initials: A
authors.lastname: Biancotto
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Stefania
authors.initials: S
authors.lastname: Capone
authors.forename: Antonella
authors.initials: A
authors.lastname: Folgori
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D000208:Acute Disease; D000818:Animals; D049109:Cell Proliferation; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019698:Hepatitis C, Chronic / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D002679:Pan troglodytes; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000502:physiology*; D014766:Viremia / Q000276:immunology*
chemical_list: D007371:Interferon-gamma