Inhibition of CXCR4-dependent HIV-1 infection by extracellular HIV-1 Tat

Certain chemokines inhibit HIV replication through binding to cell surface receptors which also act as viral coreceptors. Based on our previous observ ations that HIV-1 Tat can interact with alpha- and beta-chemokine receptors , we investigated the potential effect of extracellular Tat (ecTat) on infe ction and replication of CCR5-dependent (R5) and CXCR4-using (X4) HIV-1 str ains in primary activated peripheral blood mononuclear cells (PBMC) of unin fected donors. Receptor desensitization and binding competition studies wer e used to determine chemokine receptor binding by ecTat. Standard HIV repli cation assays based on reverse transcriptase (RT) activity determination in culture supernatants of PBMC and real time PCR for HIV-1 gag DNA were used to determine potential effects on early (entry or RT) steps of infection. ecTat bound to CXCR4 expressing monocytes and mitogen-activated PBMC, and c ompeted with the natural ligand of CXCR4, SDF-1 alpha (stromal cell-derived factor-1 alpha) in calcium mobilization assays. EcTat inhibited replicatio n of the X4 HIV-1 (LAI/IIIB strain) in activated PBMC at concentrations clo se to those of SDF-1 alpha; whereas it only modestly interfered with R5 HIV -1 (BaL) replication in PBMC. Both SDF-1 alpha and ecTat inhibited accumula tion of X4 HIV-1 gag DNA, indicating interference with viral entry and/or R T. Our data show the surprising and counter-intuitive observation that ecTa t selectively represses X4 HIV replication. This could favour spreading of R5 viruses, a condition observed in vivo immediately after transmission and in the early asymptomatic phase of infection. (C) 2000 Academic Press.