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Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection

Ronald S. Veazey¹, Per Johan Klasse², Thomas J. Ketas², Jacqueline D. Reeves³, Michael Piatak, Jr.⁴, Kevin Kunstman⁵, Shawn E. Kuhmann², Preston A. Marx¹, Jeffrey D. Lifson⁴, Jason Dufour¹, Megan Mefford¹, Ivona Pandrea¹, Steven M. Wolinsky⁵, Robert W. Doms³, Julie A. DeMartino⁶, Salvatore J. Siciliano⁶, Kathy Lyons⁷, Martin S. Springer⁸ and John P. Moore²

¹ Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA 70433
² Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
³ Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104
⁴ Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, Science Applications International Corporation Frederick, Inc./National Cancer Insititute–Frederick, Frederick, MD 20702
⁵ Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
⁶ Department of Immunology and Rheumatology, Merck Research Laboratories, Rahway, NJ 07065
⁷ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065
⁸ Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, Rahway, NJ 07065

Address correspondence to John P. Moore, Joan and Sanford I. Weill Medical College of Cornell University, Dept. of Microbiology and Immunology, 1300 York Ave., W-805, New York, NY 10021. Phone: (212) 746-4462; Fax: (212) 746-8340; email: jpm2003{at}med.cornell.edu; or Martin S. Springer, Dept. of Atherosclerosis and Endocrinology, Merck Research Laboratories, 126 East Lincoln Ave., Rahway, NJ 07065. Phone: (732) 594-4926; Fax: (732) 594-7926; email: marty_springer{at}merck.com

Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4–200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian–human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission.

Key Words: HIV • AIDS • antiretroviral therapy • microbicide • chemokine receptor

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