Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection.
Hugo R. Rosen
Submitter: Frédéric Morinet | firstname.lastname@example.org
Authors: Luana Casetti, Nathalie Mazure, and Sylvie Pillet
CHU Saint-Louis, APHP and Université Denis Diderot
Published October 14, 2013
We read with great interest the review by Dr Rosen concerning immunity to hepatitis C virus (HCV). The reason why only a fraction of infected individuals are able to clear the infection spontaneously, whereas about 80% of the infected individuals develop a chronic infection remains elusive, despite the substantial amount of immunological data available. The HCV infected chronic liver is characterized by reiteration of liver injury and current evidence suggests that angiogenesis, hypoxia and fibrogenesis are present in infected liver. Within a hypoxic area, in an experimental mouse model and in livers of human HCV cirrhotic patients, the hypoxia-inducible factors (HIFs) are stabilized and biologically active (1,2). In addition, analysis of human liver biopsy specimens revealed a correlation between elevated HCV RNA levels and increased expression of genes involved in hypoxic metabolism (3). It is now well known that hypoxia upregulates gene expression of some human viruses, notably HCV (4). The effects exerted by hypoxia on dendritic cells are still not well defined, but hypoxia upregulates expression of cytokines such as TNF and IL-1 by macrophages, which favours persistent inflammation as observed in patients with chronic HCV infections (5). Hypoxia inhibits the TH1-cell response, which indicates that cytotoxic T lymphocytes responses are ineffective in controlling HCV replication in the majority of infected patients, despite the presence in situ of HCV. In addition, hypoxia plays a dual role in HCV infected patients: enhancement of the viral load and immunosuppressive effects. In summary, it seems that hypoxia plays a central role in the immune system in combating HCV infections. Consequently, we cannot exclude that differences in expression of HIF target genes might play a role in HCV recovery, in addition to the polymorphism of interferon lambda genes.
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