Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection.

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.

• Authors: Ronald S Veazey, Per Johan Klasse, Thomas J Ketas, Jacqueline D Reeves, Michael Piatak Jr, 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 198 Issue 10 Pg. 1551-62 (Nov 17 2003) ISSN: 0022-1007 [Print] United States
• PMID: 14623909 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Retroviral Agents
• CCR5 Receptor Antagonists
• CMPD 167
• Pyrazoles
• Valine

Topics

• Animals
• Anti-Retroviral Agents (pharmacology)
• CCR5 Receptor Antagonists
• CD4-Positive T-Lymphocytes (drug effects)
• Macaca mulatta (virology)
• Pyrazoles (pharmacology)
• Simian Acquired Immunodeficiency Syndrome (drug therapy, therapy, transmission)
• Simian Immunodeficiency Virus (drug effects)
• Valine (analogs & derivatives, pharmacology)