How Do Hepatocyte MicroRNAs Play a Role in Hepatitis C Virus Replication and Pathogenesis? Emerging Hypotheses and Strategies for MicroRNA Therapeutics and Drug Development.

Abstract

Hepatitis C virus (HCV) is a major global health burden affecting millions worldwide. A deeper understanding of and theories on the mechanisms of HCV replication and pathogenesis would bode well for diagnostics and therapeutics innovation. For example, HCV is known to modulate the host genes (e.g., human hepatocytes) for its efficient viral replication. These host genes are, therefore, among the major targets for treatment of HCV infection. We report here a systematic computational study that involved biocuration of published biomedical literature and data and subsequent network analyses to identify the potential microRNA-based therapeutics targeting HCV replication. We identified 539 HCV induced unidirectionally differential regulated miRNAs and assembled 115 genes that are positively/negatively associated with HCV replication. Furthermore, interaction networks by viral proteins were constructed to reveal the regulation of these microRNA (miRNA)-modulated genes. We found hsa-miR-191-5p and choline kinase alpha (CHKA) as a significant microRNA-gene pair with relevance in glycerophospholipid metabolism, as validated by microarray expression profiles with temporal datasets. Altogether, these results provide comprehensive outline of the emerging data and hypotheses on the complex interplay between HCV and the host cells in modulating cellular miRNAs for viral proliferation. Our findings pave the way for the hypotheses that the induction of hsa-miR-191-5p or its delivery into hepatocytes or the inhibition of CHKA activity could be a potential therapeutic strategy to combat HCV-associated pathologies in the future.