Virus Entry and Virus-Host Interactions

Viruses are absolutely dependent on a host cell for their replication. The identification of host factors that interact with viral proteins, bind the viral genome, or orchestrate essential steps in the virus life cycle can suggest targets for antiviral agents. The interaction of a virion with its receptor(s) is the initial virus-host interaction and is critical for viral propagation. We have recently discovered a novel HCV co-receptor, the tight junction protein claudin-1. This adds to a growing list of essential HCV entry factors including CD81, scavenger receptor B1, and glycosaminoglycans. The early events of HCV entry into the host cell are being investigated using the recently developed HCV cell culture system, as well as with pseudoparticles in which the HCV glycoproteins, E1 and E2, decorate a defective retroviral core. We have found that HCV enters the cell by endocytosis followed by low-pH dependent fusion, and that unknown factors must prime virions to undergo this process. An understanding of the essential factors and the steps of HCV entry may inform the design of entry inhibitors and will assist in the development of small animal models.

Just as viruses commandeer cellular factors to perform essential roles in their life cycles, host cells have evolved proteins capable of targeting viral processes. Some such virus-host interactions can result in a strong innate resistance to infection. The ability of a cellular zinc-finger antiviral protein, ZAP, to inhibit Sindbis virus infection is one such host defense. Margaret R. MacDonald leads our investigations into the mechanisms by which ZAP inhibits Sindbis, as well as other members of the genus Alphavirus, and our concurrent search for other potent cellular inhibitors of viral replication. In addition to inhibitors of alphavirus replication, we are interested in finding host factors essential for the life cycle of these important model RNA viruses. We have recently shown that a putative nuclear transport factor G3BP interacts with a Sindbis replicase protein; studies are ongoing to determine the mechanistic importance of this association.