NDLI: Neurokinin-1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV-1 Infection of Macrophages in vitro

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Neurokinin-1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV-1 Infection of Macrophages in vitro

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Journal of Neuroimmune Pharmacology : Volume 1

Neurokinin-1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV-1 Infection of Macrophages in vitro

Content Provider	Springer Nature Link
Author	Wang, Xu Douglas, Steven D. Lai, Jian Ping Tuluc, Florin Tebas, Pablo Ho, Wen Zhe
Copyright Year	2007
Abstract	Despite the success of antiretroviral therapy in controlling HIV replication, treatment failure may ultimately occur in more than 50% of the individuals on antiretroviral therapy. Cellular targets offer an attractive alternative, as it may be more difficult for HIV to develop resistance to alternative cellular inhibitory pathways. We have previously shown that CP-96,345, a neurokinin-1 receptor (NK-1R) antagonist, inhibits HIV-1 infection of macrophages in vitro by downregulating CCR5 expression (Lai JP, Ho WZ, Zhan GX, Yi Y, Collman RG, Douglas SD 2001). We have now investigated the effects of a Food and Drug Administration (FDA)-approved NK-1R antagonist, aprepitant (Emend®), on HIV infection of macrophages in an in vitro system. Aprepitant is in clinical use for the prevention of nausea and vomiting associated with cancer chemotherapy or following surgical procedures.Monocytes isolated from healthy donors were cultured for 7 days and then treated with or without aprepitant (10$^{−6}$ M) for 2 h, followed by HIV infection with drug-resistant strains for 2 h. Untreated and HIV-infected macrophages were used as controls. Culture supernatants were harvested for p24 enzyme-linked immunosorbent assay (ELISA) or HIV reverse transcriptase (RT) activity at different time points after infection. R5X4 tropic and AZT-resistant strains (R5X4 tropic: A012 and A018) and RT inhibitor-resistant HIV strains (R5 tropic: TC60 and TC49) were used for infection.Aprepitant suppressed HIV Bal infection of macrophages. Treatment with aprepitant (10$^{−6}$ M) inhibited infection of macrophages with the AZT-resistant viruses (A018, A012) by 0.7 log$_{10}$. Aprepitant also suppressed infection of macrophages with RT inhibitor-resistant virus (TC 49 and TC 60) by 0.5 log$_{10}$. Furthermore, aprepitant significantly enhanced the anti-HIV activity of antiretrovirals (AZT, Efavirenz, and Indinavir) in HIV Bal-infected macrophages, and aprepitant inhibited CCR5 expression on macrophages, ranging from 50.5 to 29.6%. Donor heterogeneity was observed in antiviral activity and CCR5 receptor expression.Aprepitant is active against HIV drug-resistant isolates and enhances the anti-HIV activity of the antiretrovirals. Aprepitant downregulates CCR5 expression on macrophages. NK-1R antagonists merit further investigation as potential HIV therapeutic and immunomodulatory agents.
Starting Page	42
Ending Page	48
Page Count	7
File Format	PDF
ISSN	15571890
Journal	Journal of Neuroimmune Pharmacology
Volume Number	2
Issue Number	1
e-ISSN	15571904
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2007-01-12
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	aprepitant macrophage HIV Cell Biology Virology Pharmacology/Toxicology Immunology Neurosciences
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Allergy Pharmacology Immunology

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