Modulatory effects of the CCR5 antagonist maraviroc on microglial pro-inflammatory activation elicited by gp120.
Despite important clinical benefits of the highly active antiretroviral therapy, neurological disorders affect approximately 50% of AIDS patients. In the brain, infected microglia release pro-inflammatory mediators as well as human immunodeficiency virus type 1 (HIV-1) proteins, like the envelope protein gp120, that sustain inflammation and mediate neuronal damage. Gp120 allows the virus entry in the host cells via binding to the CD4 receptor together with a specific co-receptor (CCR5/CXCR4). The antiretroviral drug maraviroc is a CCR5 receptor antagonist, approved for the treatment of HIV-experienced patients. By interfering with a chemokine receptor, highly expressed in microglia, maraviroc has the potential to modulate their activation during HIV-1 infection. To test this hypothesis, primary cultures of rat cortical microglia were activated by gp120. Gp120(CN54) , a protein derived by macrophage (M)-tropic viruses, showed strong pro-inflammatory action, thus it was used to test the effects of maraviroc. The latter displayed opposite effects, depending on whether or not interferon-γ (IFNγ) was also present in the system. IFNγ significantly enhanced gp120 proinflammatory activity, possibly via up-regulation of CCR5 receptor expression. In this experimental paradigm, maraviroc significantly increased microglial activation, thus suggesting that its chronic use can exacerbate neuronal pathology, especially in HIV-experienced patients with higher cerebral IFNγ levels.
Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
Lucia
L
Lisi
Antonella
A
Tramutola
Andrea
A
De Luca
Pierluigi
P
Navarra
Cinzia
C
Dello Russo
D000818:Animals; D015153:Blotting, Western; D065100:CCR5 Receptor Antagonists; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology* / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015658:HIV Infections / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D000077592:Maraviroc; D017628:Microglia / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology* / Q000633:toxicity
D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D016207:Cytokines; D017931:DNA Primers; D015699:HIV Envelope Protein gp120; D012333:RNA, Messenger; D014230:Triazoles; D009569:Nitric Oxide; D007371:Interferon-gamma; D015232:Dinoprostone; D000077592:Maraviroc