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

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. W...

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Bibliographic Details
Published in:The Journal of experimental medicine 2003-11, Vol.198 (10), p.1551-1562
Main Authors: Veazey, Ronald S, Klasse, Per Johan, Ketas, Thomas J, Reeves, Jacqueline D, Piatak, Jr, Michael, Kunstman, Kevin, Kuhmann, Shawn E, Marx, Preston A, Lifson, Jeffrey D, Dufour, Jason, Mefford, Megan, Pandrea, Ivona, Wolinsky, Steven M, Doms, Robert W, DeMartino, Julie A, Siciliano, Salvatore J, Lyons, Kathy, Springer, Martin S, Moore, John P
Format: Article
Language:English
Subjects:
Animals
Anti-Retroviral Agents - pharmacology
CCR5 protein
CCR5 Receptor Antagonists
CD4-Positive T-Lymphocytes - drug effects
Human immunodeficiency virus 1
Macaca mulatta
Macaca mulatta - virology
Pyrazoles - pharmacology
Simian Acquired Immunodeficiency Syndrome - drug therapy
Simian Acquired Immunodeficiency Syndrome - therapy
Simian Acquired Immunodeficiency Syndrome - transmission
Simian immunodeficiency virus
Simian Immunodeficiency Virus - drug effects
Valine - analogs & derivatives
Valine - pharmacology
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Description
Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20031266