Hepatitis C virus fitness can influence the extent of infection-mediated epigenetic modifications in the host cells.

Introduction: Cellular epigenetic modifications occur in the course of viral infections. We previously documented that hepatitis C virus (HCV) infection of human hepatoma Huh-7.5 cells results in a core protein-mediated decrease of Aurora kinase B (AURKB) activity and phosphorylation of Serine 10 in histone H3 (H3Ser10ph) levels, with an affectation of inflammatory pathways. The possible role of HCV fitness in infection-derived cellular epigenetic modifications is not known. Methods: Here we approach this question using HCV populations that display a 2.3-fold increase in general fitness (infectious progeny production), and up to 45-fold increase of the exponential phase of intracellular viral growth rate, relative to the parental HCV population. Results: We show that infection resulted in a HCV fitness-dependent, average decrease of the levels of H3Ser10ph, AURKB, and histone H4 tri-methylated at Lysine 20 (H4K20m3) in the infected cell population. Remarkably, the decrease of H4K20m3, which is a hallmark of cellular transformation, was significant upon infection with high fitness HCV but not upon infection with basal fitness virus. Discussion: Here we propose two mechanisms ─which are not mutually exclusive─ to explain the effect of high viral fitness: an early advance in the number of infected cells, or larger number of replicating RNA molecules per cell. The implications of introducing HCV fitness as an influence in virus-host interactions, and for the course of liver disease, are warranted. Emphasis is made in the possibility that HCV-mediated hepatocellular carcinoma may be favoured by prolonged HCV infection of a human liver, a situation in which viral fitness is likely to increase.

Polymorphism of CLOCK Gene rs3749474 as a Modulator of the Circadian Evening Carbohydrate Intake Impact on Nutritional Status in an Adult Sample.

The aim of this study was to evaluate the distribution of energy intake and macronutrients consumption throughout the day, and how its effect on nutritional status can be modulated by the presence of the rs3749474 polymorphism of the CLOCK gene in the Cantoblanco Platform for Nutritional Genomics ("GENYAL Platform"). This cross-sectional study was carried out on 898 volunteers between 18 and 69 years old (65.5% women). Anthropometric measurements, social issues and health, dietary, biochemical, genetic, and physical activity data were collected. Subsequently, 21 statistical interaction models were designed to predict the body mass index (BMI) considering seven dietary variables analyzed by three genetic models (adjusted by age, sex, and physical activity). The average BMI was 26.9 ± 4.65 kg/m2, 62.14% presented an excess weight (BMI > 25 kg/m2). A significant interaction was observed between the presence of the rs3749474 polymorphism and the evening carbohydrate intake (% of the total daily energy intake [%TEI]) (adjusted p = 0.046), when predicting the BMI. Participants carrying TT/CT genotype showed a positive association between the evening carbohydrate intake (%TEI) and BMI (ß = 0.3379, 95% CI = (0.1689,0.5080)) and (ß = 0.1529, 95% CI = (-0.0164,0.3227)), respectively, whereas the wild type allele (CC) showed a negative association (ß = -0.0321, 95% CI = (-0.1505,0.0862)). No significant interaction with the remaining model variables was identified. New dietary strategies may be implemented to schedule the circadian distribution of macronutrients according to the genotype. Clinical Trial number: NCT04067921.