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. 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.
Veazey
Ronald S
RS
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.
Klasse
Per Johan
PJ
Ketas
Thomas J
TJ
Reeves
Jacqueline D
JD
Piatak
Michael
M
Kunstman
Kevin
K
Kuhmann
Shawn E
SE
Marx
Preston A
PA
Lifson
Jeffrey D
JD
Dufour
Jason
J
Mefford
Megan
M
Pandrea
Ivona
I
Wolinsky
Steven M
SM
Doms
Robert W
RW
DeMartino
Julie A
JA
Siciliano
Salvatore J
SJ
Lyons
Kathy
K
Springer
Martin S
MS
Moore
John P
JP
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*
D044966:Anti-Retroviral Agents; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D011720:Pyrazoles; D014633:Valine