The purpose of this project is to investigate basic immunological mechanisms of resistance to retroviral disease. The model employed for these studies is murine leukemia virus infection of mice and most studies are done with Friend virus (FV). Two interrelated aspects to these studies are host genetic resistance and resistance induced by vaccination. Initial infection of mice is restricted by numerous viral and host genes that function through non-immunological mechanisms. Once infection is established, genes controlling immune responses are critical for recovery. These genes include at least 4 major histocompatibility complex (MHC) genes and a non-MHC gene, Rfv-3. Thus, various aspects of resistance can be investigated by selecting mouse strains with appropriate combinations of susceptibility and resistance genes. For instance, two mouse strains which differ at the Rfv-3 resistance gene have striking differences in their ability to mount FV-specific antibody responses. Other humoral immune responses are not affected, even after FV infection. There appears to be a specific immunosuppressive effect, possibly involving interactions between FV or FV gene products and Rfv-3 gene products. This gene is of obvious interest and experiments to map this gene are ongoing. A primary interest is in the ability of FV to cause persistent infections after recovery from acute disease. Persistent viral infections are of particular interest because reactivations of persistent viruses are a major cause of mortality in patients who have become immunocompromised due to cancer or transplantation therapies, or because of infection with an immunosuppressive virus such as HIV. We have developed a mouse model to study the role of the immune system in controlling persistent FV infections and have identified CD4+ T cells as a critical mediator of such control. Experiments are being done to clone relevant CD4+ Tcells which can be used both in vitro and in vivo to study the mechanisms of presistent retrovirus control. Finally, we are using the FV model to etablish the basic immunological parameters involved in vaccine protection. Little is understood about the immunological requirements for protection against retroviral infections, and such basic knowledge may be important for the rational design of human retroviral vaccines. The vaccine studies have focused on identifying immunological determinants for protection, and studying how these determinants affect immunological and virological parameters in vivo. Experiments are being done to determine which immune cell types are involved in conferring vaccine protection. In addition, we have also been investigating whether vaccines can be effective in preventing persistent retroviral infections as well as acute disease.
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