Hepatitis C virus internal ribosome entry site RNA, 5′-NC region nucleotides 330–349 (HCV IRES (330–349))

The Hepatitis C virus (HCV) internal ribosome entry site (IRES) is a highly structured RNA element located in the 5′ non-coding (5′-NC) region of the viral genome. It is essential for the cap-independent translation of the viral polyprotein, a process that allows the virus to hijack the host's protein synthesis machinery. The specific segment spanning nucleotides 330–349 encompasses the initiator AUG start codon and constitutes Domain IV of the IRES. This region is critical for the direct recruitment and precise positioning of the 40S ribosomal subunit and the initiator tRNA at the start site to form the translation initiation complex. Due to its high sequence conservation across HCV genotypes, this region has been a primary target for antisense oligonucleotides and RNA interference (RNAi) therapeutics. Drugs such as ISIS 14803 and AVI-4065 were designed to bind this sequence, thereby inhibiting translation through steric hindrance or by inducing RNase H-mediated degradation of the viral RNA. Although these early candidates faced clinical challenges, including transient liver enzyme elevations and limited efficacy in Phase II trials, the 330–349 region remains a significant target for studying viral translation and developing novel antiviral strategies. The interaction between the IRES and the host translation machinery is a critical vulnerability in the HCV life cycle. Monitoring of viral load and liver enzymes is essential when evaluating drugs targeting this RNA motif. Overall, this target represents a paradigm for RNA-based therapeutic approaches in infectious diseases.

Other names

Hepatitis C virus internal ribosome entry site Domain IVHCV IRES initiator AUG regionHCV IRES nucleotides 330-349HCV IRES start codon region

Antisense inhibition of translation initiation and RNase H-mediated degradation of viral RNA.