Vpr- and Nef-dependent induction of RANTES/CCL5 in microglial cells.
Microglia are pivotal in the pathogenesis of AIDS dementia, as they serve as the major target of HIV infection in the CNS. In addition, activation of microglia correlates best with clinical dementia. Although the beta-chemokine RANTES/CCL5 is important in modulating HIV infection as well as cellular activation, no information is available regarding how its expression is regulated in microglia by HIV-1. Here we report that RANTES/CCL5 expression is induced in microglia by HIV-1, but that this requires infection by HIV-1. This conclusion was supported by (1) the delayed kinetics coinciding with viral replication; (2) the lack of effect of X4 viruses; (3) inhibition by the reverse transcriptase inhibitor AZT, and (4) the lack of effect of cytokine antagonists or antibodies. Interestingly, RANTES/CCL5 production was dependent on the viral accessory protein Vpr, in addition to Nef, demonstrating a novel role for Vpr in chemokine induction in primary macrophage-type cells. Furthermore, the specific p38 MAP kinase inhibitor SB203580 augmented chemokine expression in microglia, indicating a negative role played by p38. These data suggest unique features of RANTES/CCL5 regulation by HIV-1 in human microglial cells.
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D016336:Gene Products, vpr / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000821:virology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015215:Zidovudine / Q000494:pharmacology; D054311:nef Gene Products, Human Immunodeficiency Virus; D048051:p38 Mitogen-Activated Protein Kinases; D054325:vpr Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D015693:Gene Products, nef; D016336:Gene Products, vpr; D007375:Interleukin-1; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; D015215:Zidovudine; D016899:Interferon-beta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases