Figure 3.

Hypothetical model for protective and non-protective immunity upon HCV reinfection. Individuals who spontaneously clear primary HCV infection develop long-lived virus-specific memory CD4 and CD8 T cells. Such memory T cell populations are maintained by the action of homeostatic cytokines like IL-7, IL-15, and IL-21. Upon HCV reinfection, some individuals will be protected against viral persistence while others will be unprotected. (A) The protected individuals will be able to spontaneously clear the second infection with a shorter period of viremia and reduced peak viremia. Viral clearance will be accompanied by an accelerated memory T cell recall response detectable in both liver and blood. The exact characteristics of a protective response are yet to be defined in terms of breadth and quality. (B) In unprotected individuals, reinfection will be associated with a weak or late recall response and incomplete T cell-mediated control of viremia. The underlying causes of failure to resolve the reinfection despite the ability to spontaneously resolve a prior infection maybe low levels of homeostatic cytokines affecting the maintenance of memory T populations, reduced breadth, or quality of the recall response upon reinfection and increased frequency of Tregs leading to dampening of the immune response, viral persistence, and rapid exhaustion of HCV-specific T cells. Neutralizing antibodies, host genetics, and homology between the infecting viral sequences at different episodes may play a role in protection upon reinfection.