title: 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: Joan and Sanford I. Weill Medical College of Cornell University, Dept. of Microbiology and Immunology, 1300 York Ave., W-805, New York, NY 10021, USA.
authors: Ronald S
authors: RS
authors: Veazey
authors: Per Johan
authors: PJ
authors: Klasse
authors: Thomas J
authors: TJ
authors: Ketas
authors: Jacqueline D
authors: JD
authors: Reeves
authors: Michael
authors: M
authors: Piatak
authors: Kevin
authors: K
authors: Kunstman
authors: Shawn E
authors: SE
authors: Kuhmann
authors: Preston A
authors: PA
authors: Marx
authors: Jeffrey D
authors: JD
authors: Lifson
authors: Jason
authors: J
authors: Dufour
authors: Megan
authors: M
authors: Mefford
authors: Ivona
authors: I
authors: Pandrea
authors: Steven M
authors: SM
authors: Wolinsky
authors: Robert W
authors: RW
authors: Doms
authors: Julie A
authors: JA
authors: DeMartino
authors: Salvatore J
authors: SJ
authors: Siciliano
authors: Kathy
authors: K
authors: Lyons
authors: Martin S
authors: MS
authors: Springer
authors: John P
authors: JP
authors: Moore
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D008253:Macaca mulatta / Q000821:virology*; D011720:Pyrazoles / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000628:therapy / Q000635:transmission; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D044966:Anti-Retroviral Agents; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D011720:Pyrazoles; D014633:Valine