HIV infected individuals suffer from debilitating effects of the virus in the central nervous system often leading to dementia. The mechanism by which the virus induces these effects if not fully understood. In the central nervous system, the main reservoir of the virus appears to be the myelomonocytic cells comprised of macrophages and microglia. Recent fascinating research has focused on the pathogenic potential of the HIV NEF gene product. This protein has immense potential to alter the function of differentiated cells by interacting with a number of critical cellular mediators. The overall goal of this project is to further our understanding of the mechanism by which HIV causes central nervous system dysfunction. We will test the hypothesis that the NEF gene product alters the functional specificity of CNS myelomonocytic cells. We have derived a model where the expression of NEF has been targeting to the myelomonocytic compartment of transgenic mice. We will use these mice to define the functional distinctions between NEF expressing microglia and normal microglia. We will test the hypothesis that the expression of NEF alters the activation state and functional properties of microglia causing perturbations to the central nervous system function. We will define alterations in the functional properties of microglia by testing their ability to present antigen, their ability to act as targets for cytotoxic T cells and assess their capacity for proliferation and survival. Finally we will determine the impact of NEF on the ability to mount an immune response to a central nervous system pathogen, integrating what we have learned in the all of the studies, to understand the net impact of myelomonocytic-localized NEF. These studies will illuminate the mechanism whereby NEF, present in myelmonocytic cells contributes to central nervous system dysfunction associated with HIV infection.
