Adaptive immunity to the hepatitis C virus

Abstract

The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.

FIGURE 1

Three patterns of viremia have been described during the acute phase of HCV infection. In individuals who clear the infection (left panel), viremia peaks several weeks after infection when functional polyclonal CD4+ and CD8+ T responses targeting epitopes in most viral cell proteins are first detected in blood. CD8+ T cells lose expression of the coinhibitory molecule PD-1 and gain expression of the CD127 IL-7 receptor that is required for self-renewal of memory populations. Transient control of viremia can be observed for several months to a year after infection (middle panel). As indicated in the panel, these infections frequently persist, but resolution has also been observed after a prolonged period of low-level, fluctuating viremia. The end of transient virus control is associated with loss of CD4+ T helper cell function. Infections that persist without transient control of viremia have been described (right panel). T cell responses, if detected, are not sustained and usually target a limited number of epitopes. Most CD8+ T cells express high levels of PD-1. CD127 is low or absent. This exhausted phenotypic profile may be attenuated if the targeted viral epitope acquires an escape mutation (see Section IV, C1 and C2 for details).