Several viral diseases have emerged in the late 20th and early 21st centuries. This has created an urgent need to understand the mechanisms of viral entry underlying host range and pathogenicity, and a unique opportunity to exploit this knowledge to create new types of viral vectors that target therapeutic payloads to human cells with greater efficiency. Entry of enveloped viruses initiates with the binding of the envelope protein to a specific receptor on the target cell. This is followed by protein-mediated fusion which allows viral penetration of the target cell membrane. The fusion process is not energetically favorable; viral and plasma membranes are subject to strong repulsive barriers. How enveloped viruses surmount these barriers is critical to our understanding of, not only viral entry, but membrane fusion reactions and receptor cycling. My lab uses retroviruses such as gibbon ape leukemia virus (GALV) as a model system for identifying factors involved in the various stages of viral entry and for optimizing vector and target cell features that guide the retroviral vector past multiple barriers to viral entry. We have constructed and characterized a number of viral envelope proteins that bind receptor but are defective in post binding entry events. In a complementary manner we have also constructed receptor proteins that are defective in either binding or in the post-binding stages of viral entry. A compelling question connected to differences in modes of virus entry between different retroviruses is what intracellular pathways and compartments viruses must be targeted to in order to achieve transport to a compartment in which reverse transcription can occur, and from which trafficking of the provirus to the nucleus can subsequently be achieved. In collaboration with Wayne Anderson (NCI) and Jon Marsh (NIMH) we have also determined that cell signaling through protein kinases regulates post-binding viral entry. Retroviruses isolated from primates, cats, and feral rodents have many common features including their association with a high incidence of leukemias/lymphomas in their hosts and their use of similar receptor proteins including a retrovirus recently isolated from koalas that is etiologically linked to lymphomas/leukemias in these marsupials. This virus, designated KoRV has been isolated, sequenced and is highly related to GALV. We are investigating the host range and receptor utilization of KoRV (with our collaborators L. Bronham, J. McKe. P. Young. R. Tarkington, J. Hanger) using various methodology including KoRV-GALV chimeric envelope proteins. The ability to simultaneously use new knowledge about structural requirements for viral entry to engineer more efficient vectors for use in neuroscience initiatives (B. Kaplan, W. S. Young, L. Eiden), and to foil increasingly efficient emerging pathogenic viruses, will be the focus of our section
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