Interaction of host cell microRNAs with the HCV RNA genome during infection of liver cells

Abstract

It has remained an enigma how hepatitis C viral (HCV) RNA can persist in the liver of infected patients for many decades. With the recent discovery of roles for microRNAs in gene expression, it was reported that the HCV RNA genome subverts liver-specific microRNA miR-122 to protect its 5' end from degradation by host cell exoribonucleases. Sequestration of miR-122 in cultured liver cells and in the liver of chimpanzees by small, modified antisense RNAs resulted in dramatic loss of HCV RNA and viral yield. This finding led to the first successful human trial in which subcutaneous administration of antisense molecules against miR-122 lowered viral yield in HCV patients, without the emergence of resistant virus. In this review, the authors summarize the molecular mechanism by which miR-122 protects the HCV RNA genome from degradation by exoribonucleases Xrn1 and Xrn2 and discuss the application of miR-122 antisense molecules in the clinic.

Fig. 1

Hepatitis C virus (HCV) RNA genome. The HCV RNA genome consists of a single-stranded, positive-sense RNA molecule. It contains one long open reading frame (ORF) that is flanked by 5′ and 3′ untranslated regions (UTRs). Internal ribosomal entry site- (IRES-) mediated translation of the ORF gives rise to a polyprotein that is co-and posttranslationally processed into structural (C, E1, E2) and nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5B) viral proteins.

Fig. 2

MicroRNA (miRNA) processing pathway. Transcription of the primary miRNA transcript (pri-miRNA) by RNA polymerase II and pri-miRNA cleavage by the Drosha-DGCR8 complex occurs in the nucleus. The resulting precursor hairpin (pre-miRNA) of 50 to 70 nucleotides is exported from the nucleus to the cytoplasm. In the cytoplasm, the RNAse Dicer, in complex with the double stranded RNA-binding protein TRBP, cleaves the pre-miRNA hairpin to its mature length. The miRNA duplex is loaded into the RNA-induced silencing complex miRISC (Ago1–4, GW182 in mammals). One of the duplex strands is preferentially retained in miRISC, where it guides miRISC to silence target mRNAs by mRNA translational repression and deadenylation by CNOT1/CCR4.

Fig. 3

Hepatitis C virus– (HCV–) miR-122 interactions. Two molecules of miR-122 form extensive base-pairing interactions with the 5′ untranslated region (5′ UTR) of the HCV RNA genome to protect it from Xrn2-mediated 5′-3′ degradation. The viral 5′ UTR and open reading frame (ORF) are indicated.