Abstract
Background
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.
Methods
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.
Results
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 log10. Aprepitant also suppressed infection of macrophages with RT inhibitor-resistant virus (TC 49 and TC 60) by 0.5 log10. 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.
Conclusion
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.
Similar content being viewed by others
References
Annunziata P, Cioni C, Toneatto S, Paccagnini E (1998) HIV-1 gp120 increases the permeability of rat brain endothelium cultures by a mechanism involving substance P. AIDS 12:2377–2385
Azzari C, Rossi ME, Resti M, Caldini AL, Lega L, Galli L, Fico E, Vierucci A (1992) Changed levels of substance P and somatostatin in HIV-positive children. Pediatr Med Chir 14:577–581
Berger EA, Doms RW, Fenyo EM, Korber BT, Littman DR, Moore JP, Sattentau QJ, Schuitemaker H, Sodroski J, Weiss RA (1998) A new classification for HIV-1. Nature 391:240
Cheung PK, Wynhoven B, Harrigan PR (2004) 2004: which HIV-1 drug resistance mutations are common in clinical practice? AIDS Rev 6:107–116
Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, Leserman J, Petitto JM, Golden RN, Evans DL (2001) Elevated substance P levels in HIV-infected men. AIDS 15:2043–2045
Hassan NF, Campbell DE, Douglas SD (1986) Purification of human monocytes on gelatin-coated surfaces. J Immunol Methods 95:273–276
Ho WZ, Cnaan A, Li YH, Zhao H, Lee HR, Song L, Douglas SD (1996) Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. AIDS Res Hum Retrovir 12:195–198
Ho WZ, Lai JP, Zhu XH, Uvaydova M, Douglas SD (1997) Human monocytes and macrophages express substance P and neurokinin-1 receptor. J Immunol 159:5654–5660
Lai JP, Douglas SD, Ho WZ (1998) Human lymphocytes express substance P and its receptor. J Neuroimmunol 86:80–86
Lai JP, Ho WZ, Zhan GX, Yi Y, Collman RG, Douglas SD (2001) Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. Proc Natl Acad Sci USA 98:3970–3975
Lai JP, Ho WZ, Yang JH, Wang X, Song L, Douglas SD (2002) A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes. J Neuroimmunol 128:101–108
Lai JP, Ho WZ, Kilpatrick LE, Wang X, Tuluc F, Korchak HM, Douglas SD (2006) Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation. Proc Natl Acad Sci USA 103:7771–7776
Larder BA, Darby G, Richman DD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731–1734
Li Y, Douglas SD, Song L, Sun S, Ho WZ (2001) Substance P enhances HIV-1 replication in latently infected human immune cells. J Neuroimmunol 121:67–75
Wainberg MA, Turner D (2004) Resistance issues with new nucleoside/nucleotide backbone options. J Acquir Immune Defic Syndr 37:S36–S43
Willey RL, Smith DH, Lasky LA, Theodore TS, Earl PL, Moss B, Capon DJ, Martin MA (1988) In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol 62:139–147
Acknowledgments
This work was supported by the National Institutes of Health Grants P01 MH 76388 (W.Z.H.: Project 1; P.T.: Project 4; S.D.D.: Project 2, Overall P.I.) and MH 49981 (to S.D.D.). We thank Dr. Donald E. Campbell and Eric Riedel at the Flow Cytometry Core at Joseph Stokes Jr. Research Institute for the analysis of HIV entry receptor expression. We thank Dr. Kevin Lynch for statistical help. We thank Stephen Jasionowski for his editorial work.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, X., Douglas, S.D., Lai, JP. et al. Neurokinin-1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV-1 Infection of Macrophages in vitro . Jrnl Neuroimmune Pharm 2, 42–48 (2007). https://doi.org/10.1007/s11481-006-9059-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-006-9059-6