Effect of a CCR5 inhibitor on viral loads in macaques dual-infected with R5 and X4 primate immunodeficiency viruses.
Human immunodeficiency virus type 1 (HIV-1) fusion with its target cells is initiated by sequential interactions between its envelope glycoprotein, CD4, and a co-receptor, usually CCR5 or CXCR4. Small molecules that bind to CCR5 and prevent its use by R5 HIV-1 strains are now being developed clinically as antiviral drugs. To test whether a block to CCR5 promotes the replication of viruses that enter cells via CXCR4 and are associated with accelerated disease progression, we administered a small molecule CCR5 inhibitor, CMPD 167, to three macaques dual-infected with both R5 (SIVmac251) and X4 (SHIV-89.6P) viruses. CMPD 167 caused a rapid and substantial (on average, 50-fold) suppression of R5 virus replication in each animal. In two of the animals, but not in the third, a rapid, transient, 8- to 15-fold increase in the amount of plasma X4 virus occurred. In neither animal was the increase in X4 viral load sustained throughout therapy, however. These observations may have relevance for the development of CCR5 inhibitors for treatment of HIV-1 infection of humans.
Wolinsky
Steven M
SM
Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Veazey
Ronald S
RS
Kunstman
Kevin J
KJ
Klasse
Per Johan
PJ
Dufour
Jason
J
Marozsan
Andre J
AJ
Springer
Martin S
MS
Moore
John P
JP
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D065100:CCR5 Receptor Antagonists; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D008253:Macaca mulatta; D011720:Pyrazoles / Q000627:therapeutic use*; D016865:Reassortant Viruses / Q000502:physiology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D011720:Pyrazoles; D014633:Valine