(from abstract) The goal of the proposed studies is to define the virus-receptor interactions that occur during transmission and compare them with those that occur during persistent infection in the FeLV system. In FeLV infection, the transmissible form of the virus, FeLV-A appears to use distinct receptor compared with the persistent forms (FeLV-B and FeLV-T), although this receptor is not yet known. Both FeLV-T and FeLV-B evolve directly from FeLV-A and both require the sodium-dependent transporter, Pit1 for entry. The T-cell tropic FeLV-T variants require in addition a cellular accessory protein termed FeLIX. FeLIX is expressed at high levels in feline T lymphocytes and it shares homology with portions of the envelope sequence of infectious FeLV. FeLIX is the first secreted cellular factor that has been shown to be required for infection by naturally occurring retroviruses. A clearer understanding of how this soluble cellular infectivity factor interacts with the virus and the receptor may shed light on the processes of virus binding and fusion, and how these in turn regulate productive infection. Therefore, a particular focus will be in determining how the cellular factor functions to permit viral infection.
The specific aims are : 1. To define the protein-protein interactions between the FeLV-T envelope protein, the cellular receptor (Pit1) and the cellular accessory protein (FeLIX) that lead to fusion and entry by T-cell-tropic FeLV-T. 2. To define the domains of Pit1 and FeLIX that are required for FeLV-T infection, 3. To identify the receptor for FeLV-A in order to compare the virus-host cell interactions during transmission, and 4. To define the envelope domains of FeLV-A and FeLV-T that determine their unique receptor requirements. It is predicted that comparative studies of different retroviral systems may help us uncover general principles that underlie selective pressures on retroviral populations. In this regard, it is striking that in both FeLV and HIV infection, there is selection for T-cell tropic, cytopathic variants in the host, despite the many differences between these viruses.
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