Understanding the mechanisms for HIV-1 pathogenesis may be important for the development of strategies to control infection. The initiating events of viral infections are cytoadhesion and membrane fusion. Several viruses, exploit heptahelical receptors as cellular fusigens. Recent data reveals that following interaction with CD4, epitopes unmasked on gp120 env of macrophage (M)-tropic HIV-1 strains bind to a chemokine receptor, CCR5, on the surface of target cells to induce fusion of the viral and cellular lipid bilayers. Chemokine receptors are members of a receptor superfamily which have a seven transmembrane spanning topology and transmit signals through G-proteins. The hypothesis underlying this proposal is that gp120 interacts with sequence motifs in the ectodomains of CCR5 that overlap with those that confer chemokine binding specificity, but that the interaction between gp120 and ccR5 is independent of G-protein signaling. It is further postulated that the binding of gp120 to CCR5 does not transmit a signal through an interaction of its cytosolic domains with G-proteins but that this interaction results in an intramembrane signaling event transmitted through transmembrane spanning domains of the lipid bilayer. This hypothesis will be tested using mutant forms of CCR5 to dissect domains involved in chemokine binding, gp120 binding, env-mediated fusion, and chemokine-induced signaling. The second hypothesis is that there are corollaries to the CCR5 structure function analysis that are disease related. It is postulated that genetic alterations encoding a CCR5 variant with impaired reactivity with gp120 render individuals less susceptible to infection with HIV-1 or alter the course of the disease. The mechanism for the dominant negative effect of the CCR5_(794-825) """"""""knockout"""""""" allele in heterozygotes in the Caucasian population will be characterized and novel alleles will be investigated in highly exposed persistently seronegative individuals of African ancestry. The expression of CCR5 fusigenic activity in adult human and fetal mouse tissues will be determined to provide perspective for the molecular analysis of CCR5 fusion activity. Insight into the mechanisms involved in gp120-mediated fusion to target cells through CCR5 may provide novel strategies for blocking the initial event of HIV-1 infection, raising the possibility of aborting the development of AIDS following exposure to HIV-1.
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