IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

Abstract

Mutations in the core sequence of the HCV genome have been reported to influence treatment response, fibrosis progression, and hepatocarcinogenesis in Asian patients with genotype-1 chronic hepatitis C (CHC). In this issue, Miura et al. report data consistent with a causal relationship between the R70 ? Q70 core variant and hepatocellular carcinoma (HCC) risk in CHC genotype-1b patients, by the prospective evaluation of changes in the consensus sequence in the entire open reading frame between treatment failure and HCC development or end of follow-up, and validation of the initial findings in a confirmatory cohort. Furthermore, they observed an association between the IL28B genotype, which is believed to influence the immune response to viral infection, and the direction of time-dependent changes in core residue 70, with unfavorable IL28B genotypes linked to a preferential shift to the 70Q associated with HCC. Although this association needs to be validated in independent cohorts, and IL28B variants did not influence HCC risk, these results suggest that IL28B genotype might not only influence the behavior of the innate immune system in the presence of HCV genotype-1 infection but also shape the resultant viral evolution, with possible consequences on major clinical outcomes, such as HCC development, and treatment response.

HCV genotype 3: a wolf in sheep’s clothing

“…Valenti et al also reported that the rs738409 genotype, a polymorphism that influences liver fat without affecting insulin resistance and body composition, was associated with severe hepatic steatosis in patients infected with a non-3 HCV genotype, and also with fibrosis stage and cirrhosis (OR = 1.47; p = 0.002). [36] Similarly, Cai et al [37] reported that rs738409 was associated with an increased risk of steatosis in patients infected with a non-3 HCV genotype. These results suggest distinct pathogenic mechanisms in the 3 and non-3 genotypes.…”

Hepatitis C virus genetic variability and evolution

“…This result suggests that patients with the CC genotype undergo early viral evolution probably as a consequence of the selective pressure exerted by the use of interferon at the beginning of treatment. These studies raise the question of whether host genetics shapes viral evolution in response to immunity, and if the differences observed in the evolution of HCV quasispecies are implicated in the mechanism by which the IL-28B genotype influences the outcome of acute HCV infection and treatment response [97] . As previously mentioned, RNA virus populations exist as a cloud of sequence variants (continuously being generated by mutation) strongly related, therefore a better understanding of these populations within infected individuals is needed in order to apply antiviral strategies and to define critical parameters to the development of new and more effective antiviral therapies [62] .…”

Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment

“…The mechanism by which these genetic variants influence the outcome of HCV infection, i.e. whether they influence IFN-λ3 expression by affecting gene transcription or are linked a coding variant (Lys70Arg) of the IFN-λ3 protein, is still debated [ 220 , 224 ], but it seems to result in a different pattern of activation of the innate immune system against HCV infection, as determined by the different basal and IFN-α induced expression of interferon stimulated genes and inflammatory activity [ 227 , 228 ], possibly influencing viral evolution under the selective pressure of the immune system [ 229 ].…”