HIV infection begins when the virus envelope glycoprotein (Env) binds to CD4, the primary receptor molecule on the target cell surface. The virion membrane then fuses with the cell membrane, thus enabling the viral genetic material to enter the cell. Our previous work demonstrated that CD4 is not sufficient for fusion to occur; an additional """"""""fusion cofactor"""""""" is also required on the target cell. A related problem is that different genetic variants of HIV-1 have markedly distinct capabilities to infect different CD4-positive target cell types: some variants (macrophage-tropic) infect macrophages but not continuous T-lymphocyte cell lines; others (T-cell line-tropic) show the opposite specificity. The macrophage-tropic variants predominate during the early stage of infection and are the major types transmitted between individuals; the T-cell line-tropic variants appear as the infection progresses to the symptomatic stage, and probably play a special role in destruction of the immune system. Our previous work suggested that the cell type infection tropisms of different HIV variants are due the fusion specificities of the corresponding Envs. We also obtained evidence that these specificities are due to the preferential use by various Envs of distinct fusion cofactors that are differentially expressed on different CD4-expressing cell types. Using a novel cDNA screening procedure for fusion cofactor activity, we identified a molecule with properties of a fusion cofactor for T-cell line-tropic isolates; this molecule was designated """"""""fusin"""""""". Subsequently we identified another cofactor, CC CKR5, that functions preferentially for macrophage-topic variants. These cofactors appear to be members of the chemokine receptor subfamily of G protein-coupled receptors. Our findings represent major advances in our understanding of HIV entry; furthermore they suggest fundamentally new concepts about HIV transmission, disease progression, and possible means of treatment.
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