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Background & Aims: Acute hepatitis C virus (HCV) infection becomes chronic in the majority of patients. Although HCV-specific CD4 T-cell response is associated with HCV clearance, less is known about virus-specific CD8 T-cell or neutralizing antibody (nAb) responses and the role of CD4 help in their induction during acute infection. Methods: HCV-specific CD4, CD8, and HCV pseudoparticle (HCVpp) nAb responses were monitored in acutely HCV-infected patients to define their relative contributions to viral clearance. Results: Our results show that the outcome of acute hepatitis C is associated with a functional hierarchy in HCV-specific CD4 T-cell response and the scope of virus-specific, total T-cell interferon-γ response. HCV-specific CD8 T-cell response was readily detectable in acutely HCV-infected patients regardless of virologic outcome or virus-specific CD4 T-cell response. In contrast, HCVpp-specific nAbs were readily detected in patients with chronic evolution and impaired virus-specific CD4 T-cell response but not in patients who cleared infection with robust virus-specific CD4 T-cell response. Conclusions: The outcome of acute hepatitis C is associated with efficient virus-specific CD4 T-cell response(s) without which HCV-specific CD8 T-cell and heterologous nAb responses may develop but fail to clear viremia. Furthermore, HCV-specific nAb responses may not be induced despite robust virus-specific CD4 T-cell response.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The prevalence of HCC varies widely in different regions of the world. The impact of specific causes of chronic liver disease to HCC prevalence is well-established. In contrast, the contribution of the underlying genetic architecture to the risk of HCC remains undefined. Genome wide association studies have identified genetic polymorphisms associated with increased susceptibility to HCC. Our aim was to characterize evolutionary trends in the genetic profile of HCC. We hypothesized that negative selection would reduce susceptibility to genetic polymorphisms that increase risk of HCC. Methods: SNPs identified from genome wide association studies with an increased risk of HCC associated with HBV (rs17401966) or HCV (rs9275572, rs2596542) were analyzed. Genetic risk was determined from the risk odds ratio and the frequency of the risk alleles across 53 indigenous human populations across all continents using the Human Genome Diversity Project and ALFRED databases. The fixation index (Fst ) was used to describe the degree of population differentiation (low 1.5) as a measure of gene flow and similarity across subpopulations. A genetic risk score for HCC was determined based on the combined risk of five SNPs associated with increased risk of HCC [rs1800562, rs2596542, rs2267716, rs9275572 and rs17401966]. The frequency of each risk allele and the genetic risk score were correlated with geographic location and with temporal and spatial patterns of human migration. Results: A moderate increase in differentiation was noted for rs2596542 (Fst = 0.106) and rs17401966 (Fst =0.116). Both of these SNPs show an increase in allelic frequency with the most recent human migrations from East Asia, to Oceania and the Americas. In contrast, rs9275572 lacked differentiation (Fst=0.09) with stable allelic expression across populations. The percentile genetic risk score for HCC was greatest in populations from Africa (e.g. Mbuti pygymies 100, San 97), and decreased with subsequent migration into Europe and Asia through to East Asia (e.g. Lahu 1, Yi 1.5). However, a major increase was noted with most recent migrations into Oceania and the Americas (e.g. Karitiana 93.9). Conclusions: Population based studies of genomic variations provide insight into the role of migration on genetic risk for hepatocarcinogenesis. There are differences in directional differentiation of HCC risk alleles across human populations, indicating that susceptibility to HCC can be modified by factors other than genetic drift. Variations in allelic frequency of HCC associated SNPs can contribute to population-based differences in HCC prevalence, and need to be considered for developing regional strategies for screening and surveillance for HCC.