MicroRNA-122 Regulation of HCV Infections: Insights from Studies of miR-122-Independent Replication

Abstract

Despite the advancement in antiviral therapy, Hepatitis C remains a global health challenge and one of the leading causes of hepatitis related deaths worldwide. Hepatitis C virus, the causative agent, is a positive strand RNA virus that requires a liver specific microRNA called miR-122 for its replication. Unconventional to the canonical role of miRNAs in translation suppression by binding to 3'Untranslated Region (UTR) of messenger RNAs, miR-122 binds to two sites on the 5'UTR of viral genome and promotes viral propagation. In this review, we describe the unique relationship between the liver specific microRNA and HCV, the current knowledge on the mechanisms by which the virus uses miR-122 to promote the virus life cycle, and how miR-122 impacts viral tropism and pathogenesis. We will also discuss the use of anti-miR-122 therapy and its impact on viral evolution of miR-122-independent replication. This review further provides insight into how viruses manipulate host factors at the initial stage of infection to establish a successful infection.

Keywords: 5′ untranslated region; Hepatitis C virus; miR-122; miR-122-independent replication; viral tropism.

Figure 1

The miR-122 annealing pattern and hypothetical mechanistic models of miR-122 promotion of HCV propagation. (A) HCV positive strand genomic RNA with miR-122 annealing pattern. miR-122 binds to seed and auxiliary binding sites on both binding site 1 (S1) and site 2 (S2). (B) miR-122 protects RNA genome against RNA degradation machinery. (C) miR-122 binding alters 5′UTR structure to a translation favourable structure (D) miR-122 acts as a switch between viral replication and translation.

Figure 2

5′UTR mutations in full-length HCV variant genomes that can replicate in the absence of miR-122.

Figure 3

A model for the mechanism of miR-122 independent replication. miR-122-independent replication is an interplay between genome translation, replication, and stability. See text for details.

Figure 4

Predicted structures of 5′UTR of HCV and GBV-B with or without miR-122. (A) Wild type GBV-B without miR-122 (1–62 nt), (B) Wild type GBV-B with miR-122 (1–62 nt), (C) ∆4-29 mutant GBV-B without miR-122.

Figure 5

Model for miR-122 promotion of HCV: Schematic representation of infection bottleneck of HCV in the presence of different infection limiting variables.