Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion.
Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.
Veazey
Ronald S
RS
Tulane National Primate Research Center, Covington, Louisiana 70433, USA.
Klasse
Per Johan
PJ
Schader
Susan M
SM
Hu
Qinxue
Q
Ketas
Thomas J
TJ
Lu
Min
M
Marx
Preston A
PA
Dufour
Jason
J
Colonno
Richard J
RJ
Shattock
Robin J
RJ
Springer
Martin S
MS
Moore
John P
JP
D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism; D002459:Cell Fusion; D004359:Drug Therapy, Combination; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D008253:Macaca mulatta / Q000821:virology*; D008561:Membrane Fusion / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014621:Vagina / Q000187:drug effects / Q000821:virology*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D019380:Anti-HIV Agents; C477855:BMS-378806; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; C480490:CMPD 167; D015699:HIV Envelope Protein gp120; D010879:Piperazines; D011720:Pyrazoles; D019713:Receptors, CCR5; D011991:Receptors, Virus; D014633:Valine