Convergent suppression as a mechanism for persistence of hepatitis C virus in a human in vitro system

Although a causal relationship between hepatitis C virus (HCV) persistence and regulatory T cells (Tregs) has been purported, to date, no one has demonstrated how the induction of Tregs occurs. The central question of this dissertation was to address if HCV exploits known CD4+ T cell suppressive mechanisms to cause persistent infection in humans. The central finding of these studies was that naturally occurring viral variants of HCV that emerged in a major histocompatibility complex class II epitope of the nonstructural- 3 protein were acting as altered peptide ligands possibly leading to the differentiation of HCV specific CD4+ effector T cells into Tregs. To our knowledge, this work is the first demonstration of naturally occurring viral variants inducing Tregs, thereby defining an immunological niche that HCV is exploiting for persistence in humans.