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Research Aim

Neurokinin-1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV-1 Infection of Monocyte-Derived Macrophages in vitro Xu Wang, Steven D. Douglas, Jian-Ping Lai, Pablo Tebas, Janet L. Lathey, and Wen-Zhe Ho. Research Aim.

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Research Aim

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  1. Neurokinin-1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV-1 Infection of Monocyte-Derived Macrophages in vitro Xu Wang, Steven D. Douglas, Jian-Ping Lai, Pablo Tebas, Janet L. Lathey, and Wen-Zhe Ho

  2. Research Aim To investigate the role ofNeurokinin-1 Receptor Antagonist (Aprepitant) in Drug-Resistant HIV-1 Infection.

  3. Background • Respite of the success of antiretroviral therapy in maintaining control of HIV viral replication, treatment failure occurs in more than 50% of the individuals on HAART therapy. • Cellular targets are attractive because it is more difficult for HIV to develop resistance. • We have shown that NK-1R antagonist (CP-96,345) inhibits HIV-1 infection of MDM in vitro by down regulating CCR5 expression. (PNAS, 98: 3970-3975,2001)

  4. Chemical Structure of Aprepitant Aprepitant Aprepitant: FDA approved drug for the treatment of chemotherapy induced nausea

  5. Experimental Design Monocyte/Macrophage from normal subjects With or without the NK-1R antagonists treat for 2 h Different types of HIV strains infection HIV p24 assay at day 0, 3,5 7 post-infection HIV RT assay at day 4, 8,12 post-infection

  6. Inhibition of HIV (Bal) Infection of MDM by NK-1R Antagonists(10-6 M)

  7. Effect of Aprepitant on HIV Infection

  8. Dose-dependent Inhibition of Aprepitant on HIV Bal infection of MDM

  9. Effect of Aprepitant on AZT Resistant Virus Infection of MDM A012 G691-6 and A018G901-6 were kind gifts from NIH AIDS Research and Reagent Program

  10. Effect of Aprepitant on RT Inhibitor-Resistant HIV Infection of MDM TC49 and TC60 (R5 HIV strain) were kind gifts from Dr. Besty Johnston White and Dr. David Katzenstein (Stanford University)

  11. Effect of Aprepitant on HIV co-receptor (CCR5) Expression in MDM

  12. Enhancing Effect of Aprepitant on anti-HIV Drug-mediated HIV Inhibition in MDM

  13. Summary 1 • Among the NK-1R antagonists examined Aprepitant had a better inhibitory effect on HIV infection of MDM. • Aprepitant, in a dose-dependent manner, inhibits HIV R5 strain infection, partially inhibited R5X4 strain infection, and had little effect on HIV X4 strain infection.

  14. Summary 2 • Aprepitant potently inhibited the AZT-resistant strains (A018 G901-6 and A012 G691-6) infection of MDM. • Aprepitant also suppressed RT inhibitor resistant strains (TC 49 and TC 60) infection of MDM.

  15. Summary 3 • Aprepitant down-regulated CCR5, the co-receptor for HIV entry into MDM. • Aprepitant enhanced the anti-HIV activity of antiretrovirals (AZT, efavirenz, and indinavir) in MDM.

  16. Conclusion Our data suggest that NK-1R antagonists merit further investigation as potential HIV therapeutic agents

  17. Acknowledgments • This investigation was supported by MH 076388 and MH 049981 from NIH • Donald E. Campbell • Eric Riedel • Steven D. Douglas • Jian-Ping Lai • Li Song • Wenzhe Ho • Pablo Tebas Seracare BioServicesJanet L. Lathey

  18. NK-1R Antagonists: Anti-HIV Mechanisms Project 1 PI: Wenzhe Ho

  19. Table 1 – Drug Resistant Isolates to be used Isolates Biotype Resistance 139-1 SI (R5X4) AZT HIV-174V/MT2 X4 DdI, ddC HIV-1 LAI-M184V SI 3TC N119 SI (X4) Nevirapine J302 SI Saquinavir

  20. Table 2 – Antiretroviral Drugs to be Used Drug Classification Zidovudine DDC Efavirenz Lopinavir Ritonavir T20 PA-457 RT Inhibitor (NRTI) RT Inhibitor (NRTI) RT Inhibitor (NNRTI) Protease Inhibitor Protease Inhibitor Fusion Inhibitor Maturation Inhibitor

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