Background:  The neuropeptide Substance P (SP) is a major mediator of neurogenic inflammation and immunomodulatory activities within the central and peripheral nervous system. Drugs that interfere with binding of SP to the neurokinin 1 receptor NK-1, reduce the inflammatory response. Aprepitant, an NK-1 receptor antagonist, currently used clinically for controlling nausea and vomiting caused by chemotherapy, had recently been shown to also inhibit HIV infection, in part, through down-regulation of CCR5, a principal co-receptor for HIV entry in monocyte-derived macrophages. In this study, we tested additional SP antagonists for potential anti-HIV-1 activity in peripheral blood mononuclear cells (PBMC), and investigated potential synergies with other antiretroviral drugs.
Methods:  A series of SP agonists—including Aprepitant, CJ-12255, CJ-96345, RP-67,580, and L733060—were tested for potential in vitro antiviral activity against CCR5-tropic (HIV-1_Ba-L) or CXCR4-tropic (HIV-1_NL4-3) viral isolates. Viral replication in PBMC from 3 different donors was measured by quantifying p24 production (enzyme-linked immunosorbent assay). The 50% inhibitory concentration (IC₅₀) was determined for each drug. Synergistic effects of combinations of Aprepitant with representatives of each of the major classes of approved anti-HIV drugs were evaluated for inhibition of HIV-1_Ba-L in PBMC. The combination index (CI) was calculated using CalcuSyn software.
Results:  Aprepitant showed the highest antiretroviral activity (IC₅₀ 5.4 μM) of the NK-1R antagonists tested. It also exhibited good efficacy (IC₅₀ 7.95 μM±3.88) against primary infection by each major HIV-1 subtype (A, B, C, D, AE, F, G, H, and O), including CXCR4- and CCR5-tropic primary isolates propagated in PBMC, with low cytotoxicity >25 μM. Strong synergistic effect was observed for Aprepitant with ritonavir, and to a lesser degree with zidovudine and zalcitabine. No significant synergies were observed with didanosine, lamivudine, and enfuvirtide.
Conclusions:  The NK-1R antagonist, Aprepitant, has reproducible antiviral activity on a broad range of HIV isolates in PBMC culture. The fact that this drug is already used clinically to control nausea in chemotherapy and has demonstrable anti-HIV activity which is synergistic with other antiretrovirals make it an excellent candidate as a potent anti-HIV therapeutic agent. Phase I preclinical trials for use of Aprepitant as an anti-HIV agent are underway.