title: Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes.
abstract: Inhibitors of viral entry are under consideration as topical microbicides to prevent HIV-1 sexual transmission. Small molecules targeting HIV-1 gp120 (BMS-378806) or CCR5 (CMPD167), and a peptide fusion inhibitor (C52L), each blocks vaginal infection of macaques by a SHIV. A microbicide, however, must be active against multiple HIV-1 variants. We therefore tested BMS-C (a BMS-378806 derivative), CMPD167, C52L and the CXCR4 ligand AMD3465, alone and in combination, against 25 primary R5, 12 X4 and 7 R5X4 isolates from subtypes A-G. At high concentrations (0.1-1 microM), the replication of most R5 isolates in human donor lymphocytes was inhibited by >90%. At lower concentrations, double and triple combinations were more effective than individual inhibitors. Similar results were obtained with X4 viruses when AMD3465 was substituted for CMPD167. The R5X4 viruses were inhibited by combining AMD3465 with CMPD167, or by the coreceptor-independent compounds. Thus, combining entry inhibitors may improve microbicide effectiveness.
authors.affiliation: Dept of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schader
authors.forename: Juan
authors.initials: J
authors.lastname: Zurita
authors.forename: Esther
authors.initials: E
authors.lastname: Teo
authors.forename: Victoria
authors.initials: V
authors.lastname: Polonis
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D012725:Sexual Behavior; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000891:Anti-Infective Agents, Local; C477855:BMS-378806; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D023581:HIV Fusion Inhibitors; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D010879:Piperazines; D011720:Pyrazoles; D011725:Pyridines; D019718:Receptors, CXCR4; D014633:Valine