Viral internal ribosome entry site elements: novel ribosome-RNA complexes and roles in viral pathogenesis.

Abstract

Viruses have multifaceted approaches to ensure that viral genome amplification can be achieved in an efficient and, in some instances, a cell-type-specific manner. To accomplish this task, some viruses encode their own polymerases which selectively amplify the viral genomes; other viruses have evolved a variety of ways to compete directly with the host cell for factors that are needed for viral gene replication and packaging (5). However, there is one piece of macromolecular machinery in the host cell for which all viruses have to compete: the ribosome. Early in infection, the viral mRNAs have to compete with the host, not so much for ribosomes, but for the limited pool of eukaryotic initiation factors (eIFs) that mediate the recruitment of ribosomes to both viral and cellular mRNAs (10). To circumvent this competition, viruses often modify certain eIFs within infected cells so that ribosomes can be recruited selectively to viral mRNAs even though only a limited repertoire of eIFs is present (2). Of course, this strategy implies that such viral mRNAs have structural features that are distinct from most polymerase II-derived host mRNAs. For example, it was a long-standing puzzle how poliovirus, a human picornavirus, can inhibit the translation of capped host cell mRNAs when translation of its own uncapped mRNA remained uninhibited. More than a decade ago, it was discovered that poliovirus, and all other picornaviruses, contain internal ribosome entry site elements, commonly abbreviated as IRES elements, in their 5′ noncoding regions that can directly recruit ribosomal 40S subunits with a reduced set of eIFs (13, 24). The cap binding protein eIF-4E is especially dispensable for IRES activity in most viral IRES-containing mRNAs. Since then, IRES elements have been detected in many positive-stranded viral RNA genomes (9). More recently, IRESs have also been identified in Kaposi's sarcoma-associated herpesvirus, which contains a DNA genome. Specifically, a polycistronic transcript, found in all latently infected cells, is used to express the v-FLIP (FLICE-inhibitory protein) protein whose function is to counteract fatty acid synthase-induced apoptosis (1, 7). These findings have provided ample evidence that IRES elements have important functions in the viral life cycle, mostly to ensure efficient viral translation when components of the host translation machinery are limited due to virus-induced modification or host-induced antiviral responses, such as the phosphorylation of eIF-2 (9). In this minireview, I will discuss the surprising structural information we have obtained from studies on binary hepatitis C virus (HCV) IRES-40S complexes and the roles of specific canonical initiation and IRES-transacting factors (ITAFs) in translation initiation and in viral pathogenesis. I apologize for not mentioning and citing the many important contributions of other investigators who have made contributions in the viral IRES field. Due to space constraints in this minireview, I needed to focus on a few selected topics.