Hepatitis C Virus Nonstructural Region 5A Protein: A Potent Transcriptional Activator

Abstract

Hepatitis C virus (HCV) is a positive-stranded RNA virus of genomic size of approximately 10 kilobases which is distantly related to the flaviviruses and the pestiviruses of the flavivirus family [1,2]. HCV RNA is detected in the serum of patients with non-A, non-B hepatitis using the assay method of reverse transcription followed by the polymerase chain reaction (RT-PCR). RT-PCR analysis of HCV RNA shows that the majority of anti-HCV-positive patients with chronic liver disease are HCV carriers [3]. The HCV genome contains a large open reading frame encoding a polyprotein precursor of 3010–3033 amino acids and an untranslated region (UTR) at the 5′ and 3′ ends of the genome. The putative organization of the HCV genome includes the 5′ UTR, 3 structural proteins, 7 nonstructural (NS) proteins, and the 3′ UTR, in order from the 5′ end [4]. One of the NS proteins, NS5A protein, is a serine phosphoprotein with two isoforms, p56 and p58 (the hyperphosphorylated form of p56) [5]. Clinically, a close association was demonstrated between mutations in the NS5A gene of HCV-lb and the response to interferon-α in patients with chronic active hepatitis [6,7]. Recently, the NS5A protein was shown to bind interferon-induced antiviral protein, PKR (double-stranded RNA-dependent protein kinase), and inhibit its kinase activity [8]. However, the function of the NS5A protein is still not fully understood. The NS5A protein was found to possess a nuclear localization-like signal sequence and to be localized in the nuclear periplasmic membrane fraction, so it seems that it may have some function related to transcription or translation [9].