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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 for establishing persistence1. 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 protection2,3,4,5. 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 interferon-γ (IFN-γ) production, were suppressed upon HCV challenge, concomitant with quantitative and qualitative changes in regulatory T cells (Treg cells) that occurred after subinfectious HCV exposure and increased after HCV challenge. In vitro Treg 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 Treg 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.

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Figure 1: Repeated exposure to blood samples from patients positive for antibody to HCV and trace amounts of HCV induces HCV-specific T cell responses.
Figure 2: Repeated exposure to blood samples from patients positive for antibody to HCV and trace amounts of HCV suppresses T cell responses upon HCV challenge.
Figure 3: Repeated exposure to blood samples from patients positive for antibody to HCV and trace amounts of HCV suppresses intrahepatic T cell recruitment and IFN-γ production upon subsequent HCV challenge.
Figure 4: Repeated exposure to trace amounts of HCV predisposes to CD4+CD25+Foxp3+ Treg cell expansion upon subsequent HCV challenge.


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We thank T.J. Rowell, J. Fontenot and the staff at New Iberia Research Center for the care of the chimpanzees and technical support and L. Holz (NIDDK) and W. Kastenmüller (NIAID) for discussion and reading of the manuscript. This work was supported by the intramural research program of the NIDDK.

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Authors and Affiliations



S.-H.P., N.S.V. and B.R. designed the study, analyzed the data and wrote the manuscript; S.-H.P., N.S.V. and E.-C.S. processed blood and liver biopsy samples; S.-H.P. and E.-C.S. characterized T cell responses; A.B. and J.P.M. characterized Treg cell subsets by flow cytometry; N.S.V. performed virological assays and some RT-PCR assays and A.F. and S.C. challenged three control chimpanzees and performed virological analyses. All authors discussed the results and commented on the manuscript.

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Correspondence to Barbara Rehermann.

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Park, SH., Veerapu, N., Shin, EC. et al. Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection. Nat Med 19, 1638–1642 (2013).

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