HCV:CD81 Interactions Inhibit Il-2 Production by T Cells: A Novel HCV Immune Evasion Strategy

Factors contributing to the high rate of HCV chronicity are not fully understood. Interleukin 2(IL-2) is critical for the generation of broad-range antigen-specific host T-cell responses, essential for HCV clearance. Many viruses target IL-2 as part of their immune-evasion strategy, however, specific inhibition of IL-2 by HCV has not been demonstrated. CD81, a widely expressed tetraspanin, binds HCV envelope and inhibits NK cells, but, also acts as a co-stimulatory signal for IL-2 production by T cells. Thus, CD81:HCV interactions appear to favour the host and their role in viral persistence is paradoxical. We aimed to determine the role of IL-2 in HCV chronicity. We show that pre-engagement of CD81, using recombinant HCV-envelope or anti-CD81 antibodies, in a manner that mimics in vivo infection, inhibits IL-2 production by T cells. In addition HCV infectious serum produces the same inhibitory effect. We also demonstrate that hepatic IL-2 is significantly reduced in HCV compared to cirrhotic controls. These data support our model of HCV persistence whereby, CD81:HCV engagement prior to T-cell activation compromises host T cell responses. We describe a novel immune evasion strategy employed by HCV. Low-dose IL-2 in combination with current treatment regimes may lead to successful elimination of HCV.