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 to the viral genome, or orchestrate essential steps in the virus life cycle can suggest targets for antiviral drugs. Binding of a virion to its receptor(s) on the outside of the target cell is the first critical virus-host interaction. We have recently discovered two new HCV co-receptors, the tight junction proteins claudin-1 (CLDN1) and occludin (OCLN). These molecules join two previously known entry factors – CD81 and scavenger receptor B1 (SR-BI). Current work is aimed at understanding how HCV uses these four co-receptors to gain access to the interior of the cell. We have found that uptake involves endocytosis followed by low-pH dependent fusion, and that unknown factors must prime virions to undergo this process. Elucidating these first steps of HCV infection may help with 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, cells have evolved proteins capable of targeting an invading pathogen. The mammalian zinc-finger antiviral protein (ZAP) is one such host defense molecule that can stop some viruses in their tracks. Research Associate Professor Margaret R. MacDonald leads investigations into the mechanisms by which ZAP inhibits Sindbis virus, a member of the family Togaviridae. Recent work has shown that two or more ZAP proteins work together to block translation of the incoming Sindbis genome. We have also found that factors involved in cellular stress (G3BP1 and G3BP2) can interact with the Sindbis replication machinery and limit viral polyprotein expression. We are continuing to search for new antiviral proteins that may one day be exploited for drug development.