Repeated exposure to trace amounts of hepatitis C virus suppresses T-Cell responses to subsequent high-dose HCV challenge via induction of regulatory T Cells

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIDDK	INFECTDIS-11

Authors

• SH Park
• NS Veerapu
• B Rehermann

Abstract

Clearance of hepatitis C virus (HCV) infection depends on T cells but it is unclear whether protective immunity exists in humans. It has been proposed that HCV-specific T cells observed in some seronegative injection drug users confer immune protection. To test this hypothesis we repeatedly infused two chimpanzees with human plasma containing trace amounts of HCV and a control chimpanzee with HCV RNA-negative plasma, evaluated immune responses and challenged with high-dose HCV. The two HCV-exposed chimpanzees remained HCV RNA-negative but developed HCV-specific T cells that were not detected in the control chimpanzee. Unexpectedly, high-dose HCV challenge did not boost but decreased these T-cell responses. Furthermore, induction of new HCV-specific T cells was suppressed, and intrahepatic CD8 and IFN-g mRNA levels remained significantly decreased compared to the control chimpanzee. Repeated low-dose HCV exposure expanded functional CD4+CD25+Foxp3+ Tregs in blood and liver, which were further amplified during high-dose HCV challenge. The increased Treg frequency corresponded to increased intrahepatic Foxp3, IL-10, TGF-b and B7-H4 mRNA levels. Thus, repeated exposure to trace amounts of HCV expands functional Tregs that suppress T-cell responses to high-dose HCV challenge. This mechanism may diminish the efficiency of candidate vaccines in frequently exposed, high-risk populations.

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