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

被引:64
作者
Ghezzi, S [1 ]
Noonan, DM
Aluigi, MG
Vallanti, G
Cota, M
Benelli, R
Morini, M
Reeves, JD
Vicenzi, E
Poli, G
Albini, A
机构
[1] Ist Sci San Raffaele, DIBIT, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy
[2] Ist Nazl Ric Canc, Ctr Biotecnol Avanzate, Mol Biol Lab, I-16132 Genoa, Italy
[3] Ist Nazl Ric Canc, Ctr Biotecnol Avanzate, Modulo Progress Neoplast, I-16132 Genoa, Italy
[4] UCL, Dept Mol Pathol, Winder Inst Med Sci, Wohl Virion Ctr, London, England
关键词
acute infection; chemokines; pathogenesis; virus-cell interactions; HIV-1 Tat protein; Tat; HIV-1; CXCR4; entry; infection;
D O I
10.1006/bbrc.2000.2523
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Certain chemokines inhibit HIV replication through binding to cell surface receptors which also act as viral coreceptors. Based on our previous observations that HIV-1 Tat can interact with alpha- and beta-chemokine receptors, we investigated the potential effect of extracellular Tat (ecTat) on infection and replication of CCR5-dependent (R5) and CXCR4-using (X4) HIV-1 strains in primary activated peripheral blood mononuclear cells (PBMC) of uninfected donors. Receptor desensitization and binding competition studies were used to determine chemokine receptor binding by ecTat. Standard HIV replication 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 competed with the natural ligand of CXCR4, SDF-1 alpha (stromal cell-derived factor-1 alpha) in calcium mobilization assays. EcTat inhibited replication of the X4 HIV-1 (LAI/IIIB strain) in activated PBMC at concentrations close 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 accumulation of X4 HIV-1 gag DNA, indicating interference with viral entry and/or RT. Our data show the surprising and counter-intuitive observation that ecTat 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.
引用
收藏
页码:992 / 996
页数:5
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