Host response to lentiviral infection

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Cats are susceptible to infection with a retrovirus (feline immunodeficiency virus = FIV) that causes AIDS in cats like HIV causes AIDS in humans. Both viruses infect helper T-lymphocytes, induce immunodeficiency and eventually cause death of the host. Infection of cats by FIV is the only naturally occurring model of HIV infection, and very suitable for addressing questions difficult to investigate in humans. Illness and death from infection with HIV remain enormous problems throughout the world, but vaccines against HIV to date have uniformly failed. Highly active anti-retroviral therapy is effective for treating HIV infections, but is not accessible to the vast majority of people. The HIV epidemic arose from transmission of a chimpanzee retrovirus to humans several hundred years ago, most likely through exchange of blood associated with hunting. The lesser-known FIV epidemic arose from transmission of a retrovirus from wild cats to domestic cats several thousand years ago. A long-standing conundrum in understanding of retroviral disease is that infection in chimpanzees and wild cats does not cause disease, while in humans and cats infections are fatal. Knowledge is emerging to indicate that the manner in which the host deals immediately after exposure with the virus is probably most important for determining whether and how quickly immunodeficiency and death will occur. Host responses in the first days after exposure are mediated by innate, or pre-existing, host responses. Some components of this host response generally sense any virus and initiate an inflammatory response, while other factors sense specific viruses such as HIV or FIV. Such virus-specific host “restriction factors” evolve genetically more quickly than other host genes, and appear have become lost or ineffective in humans and cats, but remain active in apes and wild cats. In this research we will determine why cats fail to restrict FIV replication. First, we examine whether the virus itself incorporates factors that suppress immune responses. This will be accomplished by generating highly purified virus particles, analysis of their proteins by mass spectrometry, search of databases to identify the non-viral proteins, and determination of the function of such proteins. We then examine within the host what genes respond to an inflammatory stimulus in dendritic cells (which are the first cells that capture virus invading across mucous membranes) and lymphocytes (which are the main viral reservoir during development of immunodeficiency). These genes will be scrutinized for possible interaction with FIV, and specifically the sites within the restriction factor that bind to virus will be detailed to the molecular level. Then, candidate genes that code for restriction factors will be cloned, their proteins produced in vitro, and then examined to precisely determine their mechanism of viral interference in cells. Finally, it will be resolved whether viruses with higher susceptibility to inhibition by cellular factors cause lower viral burdens and less immunodeficiency and disease in cats. These investigations aim to determine 1) the presence of host anti-FIV factors; 2) their significance to the FIV life cycle and pathogenicity; 3) the mechanisms of interference with viral infection; and 4) the relevance of such responses to outcomes of infection. Results will yield insight widely applicable to understanding of retroviral-host adaptation and evolution, and to generation of new therapeutic and prophylactic targets. The proposed research addresses fundamental questions in the natural sciences, specifically virology and immunology, which may have eventual impact on advancing human health. NSERC is the appropriate funding agency for this research.