Immunological determinants of the outcomes from primary hepatitis C infection

Abstract

Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection, determined by a complex set of virus-host interactions. The focus of this review is the host mechanisms that facilitate clearance. Strong evidence points to characteristics of the cellular immune response as the key determinants of outcome, with evidence for the coordinated effects of the timing, magnitude, and breadth, as well as the intra-hepatic localisation of CD4+ and CD8+ T cell responses being critical. The recent discovery of viral evasion strategies targeting innate immunity suggests that interferon-stimulated gene products are also important. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals with acute HCV.

Novel Infectious cDNA Clones of Hepatitis C Virus Genotype 3a (Strain S52) and 4a (Strain ED43): Genetic Analyses and In Vivo Pathogenesis Studies

“…In one animal (CH5300), cellular immunity developed early, targeted multiple HCV proteins, and was associated with transient control of viral replication, while in the other animal (CH5276), a narrow response that was delayed for months provided no apparent control of viremia. While these divergent patterns of cellular immunity and virus replication have been reported (2,15,27,57,67,75), two unique aspects of acute infection are highlighted by the present study. First, CD4…”

“…3). This pattern was typically observed in animals that cleared HCV, but it has also been observed in animals that subsequently developed persistent infection (15,27,57,67); it has not been entirely clarified which immunological and/or viral features are determining such different outcomes. In other animals with persistent infection, as was observed for CH5276, HCV RNA titers remained relatively stable during the acute phase of infection (15,27,57,67).…”

The Autophagosomal SNARE Protein Syntaxin 17 Is an Essential Factor for the Hepatitis C Virus Life Cycle

“…It is assumed that an infected hepatocyte produces about 1,000 virions per day but only 50 are released, raising the question about the fate of the remaining 950 virions (16,17). Moreover, all structural proteins are formed on the basis of a polyprotein.…”

“…It is established that HCV hijacks steps of the autophagic pathway (22,23,38). In light of the observation that the number of viral particles formed is much greater than the number of infectious viral particles that are finally released (16,17), regulation of the fusion between autophagosomes and lysosomes might fulfill a key function controlling the release of HCV.…”

“…However, if the Rab9 binding site in TIP47 is destroyed, TIP47 still binds to the viral particle but the complex is trapped in the autophagosomallysosomal compartment (15). Only a small fraction of the de novosynthesized structural proteins/viral particles is indeed released as infectious viral particles, while the majority of the de novo-synthesized particles is intracellularly retained and degraded (16,17).…”