HCV-2a NS5A downregulates viral translation predominantly through domain I

Abstract Hepatitis C virus (HCV) non-structural protein NS5A is a multifunctional protein with critical roles in viral replication and assembly. We previously showed that HCV-1b NS5A downregulates viral translation only in the presence of the poly(U/UC) tract in 3′UTR. As NS5A of different HCV genotypes may have different functions or carry out the same functions through genotype-specific mechanisms, we investigated the effect of HCV-2a NS5A on viral translation. We found that HCV-2a NS5A downregulates RNA translation of both HCV-2a and -1b, whereas the effect of HCV-1b NS5A is limited to HCV-1b only. In addition, individual regions of 3′UTR are not required for HCV-2a NS5A to downregulate viral RNA translation. We also found that HCV-2a NS5A inhibits capped mRNA translation. Mapping experiments showed that the translation downregulation by HCV-2a NS5A is predominantly mediated by domain I. Furthermore, we found that the integrity of serine-146 residue plays an important role in translation downregulation by NS5A. Our results increased our understanding on genotype-specific functions of HCV NS5A.