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

Ronald S. Veazey, Per Johan Klasse, Thomas J. Ketas, Jacqueline D. Reeves, Michael Piatak, Kevin Kunstman, Shawn E. Kuhmann, Preston A. Marx, Jeffrey D. Lifson, Jason Dufour, Megan Mefford, Ivona Pandrea, Steven M. Wolinsky, Robert W. Doms, Julie A. DeMartino, Salvatore J. Siciliano, Kathy Lyons, Martin S. Springer, John P. Moore*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1551-1562
Number of pages12
JournalJournal of Experimental Medicine
Volume198
Issue number10
DOIs
StatePublished - Nov 17 2003

Keywords

  • AIDS
  • Antiretroviral therapy
  • Chemokine receptor
  • HIV
  • Microbicide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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