Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus.

Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute previously associated with formation of large-scale RNA structure in their genomic RNA. We developed novel methods to analyze and visualize genome-scale ordered RNA structure (GORS) predicted from the increasingly large data sets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localized exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem-loop elements involved in genome folding were structurally poorly conserved, even between subtypes 1a and 1b. Dynamic remodeling was further evident from comparison of HCV strains in different host genetic backgrounds. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies, and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the IFNL4 gene compared to the CC (nonexpressing) allele. These structural and compositional associations with expression of interferon-λ4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represent an important new element in RNA virus evolution and the adaptive interplay between virus and host.

Antiretroviral therapy and liver disease progression in HIV and hepatitis C co-infected patients: a systematic review and meta-analysis.

BACKGROUND: HIV co-infection exacerbates hepatitis C disease, increasing the risk of cirrhosis and hepatitis C-related mortality. Combination antiretroviral therapy (cART) is the current standard treatment for co-infected individuals, but the impact of cART and antiretroviral (ARV) monotherapy on liver disease in this population is unclear. We aimed to assess the effect of cART and ARV monotherapy on liver disease progression and liver-related mortality in individuals co-infected with HIV and chronic hepatitis C. METHODS: A systematic review with meta-analyses was conducted. MEDLINE and EMBASE bibliographic databases were searched up to September 2015. Study quality was assessed using a modified Newcastle-Ottawa scale. Results were synthesised narratively and by meta-analysis. RESULTS: Fourteen observational studies were included. In analyses that adjusted for potential confounders, risk of liver-related mortality was significantly lower in patients receiving cART (hazard ratio/odds ratio 0.31, 95 % CI 0.14 to 0.70). Results were similar in unadjusted analyses (relative risk 0.40, 95 % CI 0.29 to 0.55). For outcomes where meta-analysis could not be performed, results were less consistent. Some studies found cART was associated with lower incidence of, or slower progression of liver disease, fibrosis and cirrhosis, while others showed no evidence of benefit. We found no evidence of liver-related harm from cART or ARV monotherapy compared with no HIV therapy. CONCLUSIONS: cART was associated with significantly lower liver-related mortality in patients co-infected with HIV and HCV. Evidence of a positive association between cART and/or ARV monotherapy and liver-disease progression was less clear, but there was no evidence to suggest that the absence of antiretroviral therapy was preferable.