Glycospingolipids (GSLs) have been implicated as fusion co-factors for human immunodeficiency virus (HIV) the causative agent of AIDS. The overall goal of the proposed research is to determine the role(s) of GSLs in the interaction of HIV-1-associated gp120 with different cell types of the central nervous system (CNS) or models thereof, and to use that information to develop possible inhibitors of that interaction. Emphasis is placed on CNS cells or possible models thereof because many individuals infected with HIV-1 eventually develop HIV-1-associated dementia (HAD) in the absence of opportunistic infection.
The specific aims of this proposal are to: 1) identify which GSL(s) is/are the ligand(s) for HIV-1-associated gp120. Experiments will be done to confirm that GSLs are necessary for HIV-1 entry and, in those instances where they are necessary, the GSLs adhered to by HIV-1 will be identified. 2) determine the contribution of the GSL saccharide and ceramide moieties to interactions with HIV-1-associated gp120. Experiments will be carried out to determine whether the saccharide portion of each GSL adhered to by HIV-1 can inhibit HIV-1 adherence to the GSL immobilized on plastic or whether a """"""""multivalent"""""""" saccharide or the ceramide portion per se is needed. 3) determine whether the inhibitor of HIV-1 associated gp120-mediated adherence to a GSL is able to inhibit gp120-mediated entry of the virus into cells expressing the GSL. The effectiveness of the inhibitor identified in the 2nd aim at blocking infection will be monitored using microglia and asrtrocytes. The effectiveness of the virus at inducing apoptosis in neuroblastoma cells in the presence and absence of inhibitor will also be ascertained. The results should indicate the portion of the GSL(s) recognized by HIV-1. They may also provide the basis for development of an inhibitor able to block adherence of HIV-1 to its GSL fusion co-factor thereby blocking its entry into the cell.
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