Opposing positive and negative regulation of T cell activity during viral persistence

Vigorous T cell responses are crucial for the control of viral infections. However, in some instances antiviral T cell responses are suppressed resulting in viral persistence. The loss of T cell function is regulated by a variety of host-based immunosuppressive factors that directly inhibit antiviral immunity and prevent viral clearance. Nevertheless, residual levels of T cell activity are actively sustained to exert an important degree of control over persistent virus replication. How T cells are differentially regulated in response to persistent infection and the positive and negative signals that result in these divergent functional responses are just now beginning to come to light. Unraveling this complex dual counter-regulation of T cell responses during persistent virus infection will provide valuable insight toward the development of therapies to overcome immune suppression and stimulate T cell responses to eliminate persistent viral replication. In this review we will highlight this emerging field and discuss the complex interplay between immune-modulatory factors that suppress and sustain antiviral immunity to control and in some instances eliminate persistent viral replication.