Modulatory effects of the CCR5 antagonist maraviroc on microglial pro-inflammatory activation elicited by gp120.

Abstract

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.

• Authors: Lucia Lisi, Antonella Tramutola, Andrea De Luca, Pierluigi Navarra, Cinzia Dello Russo
• Journal: Journal of neurochemistry (J Neurochem) Vol. 120 Issue 1 Pg. 106-14 (Jan 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 22017448 (Publication Type: Journal Article)
• Copyright: © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Chemical References

• CCR5 Receptor Antagonists
• Cyclohexanes
• Cytokines
• DNA Primers
• HIV Envelope Protein gp120
• RNA, Messenger
• Triazoles
• Nitric Oxide
• Interferon-gamma
• Dinoprostone
• Maraviroc

Topics

• Animals
• Blotting, Western
• CCR5 Receptor Antagonists
• Cell Survival (drug effects)
• Cells, Cultured
• Cyclohexanes (pharmacology, toxicity)
• Cytokines (biosynthesis)
• DNA Primers
• Dinoprostone (metabolism)
• HIV Envelope Protein gp120 (antagonists & inhibitors, pharmacology)
• HIV Infections (pathology)
• Inflammation (pathology)
• Interferon-gamma (pharmacology)
• Macrophage Activation (drug effects)
• Maraviroc
• Microglia (drug effects)
• Nitric Oxide (metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Real-Time Polymerase Chain Reaction
• Triazoles (pharmacology, toxicity)