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Significance of this study What is already known on this subject?
Host factors are considered to be an important component in the control of HCV infection.
The HLA genes, as well as the innate immune genes IFNL3 and KIR , are considered to be important determinants of viral outcomes, however, their interaction with each other has not been well studied.
A single source outbreak of HCV provides us with a unique opportunity to understand the nature of these genetic influences in more detail as confounding factors are controlled.
What are the new findings?
HLA Class I and II genes are significantly associated with viral outcomes even when the profound impact of IFNL3 and KIR2DS3 are considered.
There is no evidence of a genetic interaction effect between the HLA Class I and II alleles and IFNL3 .
There is, however, a clear additive effect between the different genes indicating likely independent and separate but cumulative immune events.
The results also indicate that there may be a differential effect with respect to HLA Class I alleles and viral outcomes according to the nature of the innate immune response.
These data support a critical role for the adaptive immune response alongside the innate immune response in the control of HCV infection.
How might it impact on clinical practice in the foreseeable future?
These data provide important insights to the immunopathogenesis of this illness which is of direct relevance to HCV vaccine studies and design.
Introduction
Infection with HCV is one of the leading causes of liver-related mortality globally. Most persons who are exposed to HCV will develop persistent infection; however, a proportion (20-30%) spontaneously clear infection. Those patients with chronic HCV infection are at risk of developing liver cirrhosis and/or hepatocellular carcinoma. 1 Much effort has aready been invested in understanding the factors that determine the differing outcomes in individuals but disentangling the impact of host and viral factors has been difficult. One of the reasons for this is that HCV exhibits substantial genetic heterogeneity as a consequence of its error-prone polymerase enzyme, 2 3 and high replication rates with virion production exceeding 10 12 particles per day. 4
Nonetheless, there are clear reports of host factors that are influential in determining viral outcome. The cellular immune...