TAT PROTEIN INDUCES HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) CORECEPTORS AND PROMOTES INFECTION WITH BOTH MACROPHAGE-TROPIC AND T-LYMPHOTROPIC HIV-1 STRAINS

Chemokine receptors CCR5 and CXCR4 are the primary fusion coreceptors utilized for CD4-mediated entry by macrophage (M)- and T-cell Line (T) -tropic human immunodeficiency virus type 1 (HIV-1) strains, respectiv ely, Mere we demonstrate that HN-I Tat protein, a potent viral transac tivator shown to be released as a soluble protein by infected cells, d ifferentially induced CXCR4 and CCR5 expression in peripheral blood mo nonuclear cells. CCR3, a less frequently used coreceptor for certain M -tropic strains, was also induced. CXCR4 was induced on both lymphocyt es and monocytes/macrophages, whereas CCR5 and CCR3 were induced on mo nocytes/macrophages but not on lymphocytes, The pattern of chemokine r eceptor induction by Tat was distinct from that by phytohemagglutinin. Moreover, Tat-induced CXCR4 and CCR5 expression was dose dependent, M onocytes/macrophages were more susceptible to Tat-mediated induction o f CXCR4 and CCR5 than lymphocytes, and CCR5 was more readily induced t han CXCR4. The concentrations of Tat effective ill inducing CXCR4 and CCR5 expression were within the picomolar range and close to the range of extracellular Tat observed in sera from HIV-1-infected individuals . The induction of CCR5 and CXCR4 expression correlated with Tat-enhan ced infectivity of M- and T-tropic viruses, respectively, Taken togeth er, our results define a novel role for Tat in HIV-1 pathogenesis that promotes the infectivity of both M- and T-tropic HIV-1 strains in pri mary human leukocytes, notably in monocytes/macrophages.