Berger EA; Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Individual HIV-1 isolates vary markedly in their tropisms for infecting different CD4-positive target cell types. Some isolates (macrophage-tropic) infect macrophages but not continuous T-lymphocyte cell lines while others (T-cell line-tropic) display the opposite preference. We have shown that the cytotropisms, of different HIV variants are due to the inherent fusion specificities of the corresponding Envs, which in turn result from the ability of each Env to use distinct "fusion cofactors" that are differentially expressed on various CD4-positive cell types. Using a novel functional cDNA screening method, we identified a fusion cofactor for T-cell line-tropic isolates; we designated this molecule "fusin". Subsequently we identified another cofactor, CCR5, that functions preferentially for macrophage-tropic variants. Both cofactors are members of the chemokine receptor family of G protein-coupled receptors. Primary HIV-1 isolates from diverse genetic subtypes were found to function with CCR5 and/or fusin (and is some cases with other chemokine receptors). We determined that signalling through G proteins is not required for fusion cofactor activity. Studies are in progress to identify functional determinants in the Env/cofactor interactions. We observed that fusin and CCR5 expression are regulated differently upon T-cell activation, suggesting implications for HIV replication in vivo. Of particular interest are findings indicating that genetic alterations in the fusion cofactors can directly influence susceptibility to HIV infection, and possibly rates of disease progression in infected persons. The identification of the fusion cofactors suggests ways to develop small animal models for HIV infection as well as novel therapeutic agents.
Keywords: AEGIS, Tropism, Receptors, CXCR4, HIV-1, Antigens, CD4, Receptors, Chemokine, Macrophages, HIV Infections, Virus Replication, T-Lymphocytes, Carrier Proteins, Cell Line, Anti-HIV Agents, virology, AIDS
