Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action.
Poly(styrene 4-sulfonate), cellulose sulfate, polymethylenehydroquinone, and PRO 2000 are sulfated or sulfonated polymers (SPs) under development as topical microbicides. They are presumed to work through similar mechanisms of action, although to date there has been no extensive comparison of their anti-human immunodeficiency virus activities. To determine whether any of these candidate microbicides offers a potential advantage, their in vitro activities, mechanisms of action, stabilities in biological secretions, and toxicities were compared. All four compounds were found to be active against X4, R5, and dualtropic primary isolates and against X4 and R5 laboratory-adapted strains in CD4+ T cells, macrophages, and single-coreceptor cell lines. Our single-cycle experiments using pseudotyped virus suggest that all four SPs function at the binding and entry stages of the viral life cycle but differ in degree of postentry effect. Surface plasmon resonance analyses demonstrate that SPs bind to X4 and R5 monomeric glycoprotein 120 with similar high binding affinities. When mixed with cervicovaginal lavage fluid, SPs maintain inhibitory activity at concentrations achievable in formulations.
Scordi-Bello
Irini A
IA
Department of Medicine, Mount Sinai School of Medicine, Box 1090, New York, NY 10029, USA.
Mosoian
Arevik
A
He
Cejiang
C
Chen
Yiban
Y
Cheng
Yang
Y
Jarvis
Gary A
GA
Keller
Marla J
MJ
Hogarty
Kathleen
K
Waller
Donald P
DP
Profy
Albert T
AT
Herold
Betsy C
BC
Klotman
Mary E
ME
D000287:Administration, Topical; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001826:Body Fluids / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000821:virology; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D007202:Indicators and Reagents; D008264:Macrophages / Q000821:virology; D011108:Polymers / Q000008:administration & dosage / Q000494:pharmacology; D013431:Sulfates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D020349:Surface Plasmon Resonance; D014621:Vagina / Q000821:virology
D019380:Anti-HIV Agents; D006023:Glycoproteins; D007202:Indicators and Reagents; D011108:Polymers; D013431:Sulfates; D013451:Sulfonic Acids