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02610_1 WHI-07 PREVENTS VAGINAL AND RECTAL TRANSMISSION OF FELINE IMMUNODEFICIENCY VIRUS INFECTION IN CATS DCruz Osmond J. WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5-(p-bromophenyl)-methoxy alaninyl phosphate] is a novel nontoxic dual-function aryl phosphate derivative of zidovudine (ZDV/AZT) with potent anti-HIV and contraceptive activities. WHI-07 was active against the feline immunodeficiency virus (FIV). This study evaluated whether topical application of WHI-07 as a single agent and in combination with an organometallic vanadium complex, vanadocene dithiocarbamate (VDDTC) via a nontoxic gel-microemulsion can block vaginal as well as rectal transmission of feline AIDS (FAIDS) by chronically FIV-infected feline T cells in the natural host model. Genital transmission of FIV was monitored in recipient cats by the appearance of viral antibodies to FIV gag proteins and by virus isolation of blood leukocytes measured by FIV reverse transcriptase activity and FIV-specific polymerase chain reaction. Microbicide activity was considered effective when the treated cats did not show evidence of FIV infection for up to 18 weeks post challenge. An aggregate analysis of 46 specific pathogen-free cats revealed that a single dose of the infected cell inoculum efficiently transmitted FIV infection when delivered into the vagina (100%) or rectum (66%). Pretreatment of the vagina or rectum with 2% WHI-07 alone or in combination with 0.25% vanadocene dithiocarbamate (VDDTC) significantly (P = 0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIV-infected feline T cells). Collectively, using the vaginal and rectal transmucosal model for FAIDS, our studies demonstrated that WHI-07 either alone or in combination with a vanadocene has clinical potential for the development of a contraceptive anti-HIV microbicide for sexually active women. Supported by: NIH grants HD 37357, HD 42884, HD 42889 and amfAR grant 02667. Dr. Osmond J. DCruz |
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