The main hypothesis of this Program Project is that neurotropic and macrophage tropic strains of SIV and HIV are closely related phenotypically and genetically. Infection with SIV and HIV results in clinical disease characterized by severe immunosuppression and neurological disorders. The cellular tropism of the viruses determines whether CNS infection and neurological disease occurs. Genetic factors appear to be major determinants of the cellular tropism of SIV and HIV. However there is evidence that host cell factors are also important. Recent data indicates that adhesion molecules on host cells play important accessory roles in the infectivity of these viruses. We have now shown that SIV and HIV carry major leukocyte adhesion molecules on their surfaces. The central hypothesis of this proposal is that host cell adhesion molecules acquired by SIV and HIV may affect the binding, infectivity, and cellular tropism of the viruses. The objective of the proposed project is to obtain data to support this hypothesis.
The specific aims of the project are: 1) To define the nature of the association between host cell adhesion molecules and SIV and HIV using immunogold electron microscopy, qualitative and quantitative virus capture assays, and flow cytometry; 2) To determine the effect on virus binding and infectivity of adhesion molecules acquired by SIV and HIV using radiolabeled and biotinylated virus in competitive antibody binding assays and by following the kinetics of infection with and without contributions to virus binding by adhesion molecules; 3) To determine if adhesion molecules mediate the binding of SIV and HIV to neural cells or extracellular matrix components by using these cells and ECM components in virus binding assays. Survival of marginated virus will be followed over several weeks. Soluble ligands and monoclonal antibodies will be used to determine the contribution of adhesion molecules to virus binding; 4) To determine the effect of adhesion molecule acquisition by SIV and HIV on virus neutralization by SIV+-macaque or AIDS sera using virus prepared in host cells with varying levels of adhesion molecule expression in serum neutralization assays. Enhancement of serum neutralization of neurotropic and non-neurotropic viruses by adhesion molecule-specific antibodies will be evaluated. 5) To determine whether lymphocyte-tropic, macrophage-tropic/non-neurotropic, and macrophage- tropic/neurotropic strains of SIV differ in their acquisition of host adhesion molecules using qualitative and quantitative virus capture assays and by immunoelectron microscopy. Viruses isolated from CNS and other tissues of infected macaques will be studied to determine if tissue-specific acquisition of adhesion molecules by SIV occurs.
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