Antiretroviral spermicide WHI-07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats
Antiretroviral spermicide WHI-07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats
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DOI：
10.1128/aac.48.4.1082-1088.2004
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发表时间：
2004-04-01
影响因子：
4.9
通讯作者：
Uckun, FM
中科院分区：
文献类型：
--
作者：
D'Cruz, OJ;Waurzyniak, B;Uckun, FM
WHI-07 [5-溴-6-甲氧基-5，6-二氢-3 '-叠氮胸苷-5'-（对溴苯基）-甲氧基丙氨酰磷酸酯]是一种新型双功能齐多夫定芳基磷酸酯衍生物，具有抗人类免疫缺陷病毒（HIV）和杀精子活性。WHI-07对猫免疫缺陷病毒（FIV）有活性。本研究评估了WHI-07作为单一药剂以及与有机金属钒络合物二硫代氨基甲酸二茂钒（VDDTC）组合的局部施用是否通过无毒凝胶微乳液可以阻断猫AIDS（FAIDS）在自然宿主模型中通过慢性FIV感染的猫T细胞的阴道和直肠传播。通过FIV Gag蛋白的病毒抗体的出现和通过FIV逆转录酶活性和FIV特异性PCR测量的血液白细胞的病毒分离，在受体猫中监测FIV的生殖器传播。当给药猫在攻毒后长达18周未显示FIV感染证据时，认为杀微生物活性有效。对46只无特定病原体的猫进行的综合分析显示，单剂量的感染细胞接种物在递送到阴道（100%）或直肠（66%）时有效地传播FIV感染。用2%WHI-07单独或与0.25%VDDTC组合预处理阴道或直肠显著（P=0.004）保护猫免受高感染性接种物（700万FIVBangston感染的猫T细胞）的生殖器传播。总的来说，使用阴道和直肠经粘膜模型用于FAIDS，我们的研究表明，WHI-07单独或与二茂钒组合具有开发用于性活跃女性的双功能抗HIV杀微生物剂的临床潜力。
WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxy alaninyl phosphate] is a novel dual-function aryl phosphate derivative of zidovudine with potent anti-human immunodeficiency virus (HIV) and spermicidal 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 as measured by FIV reverse transcriptase activity and FIV-specific PCR. Microbicidal activity was considered effective when the treated cats did not show evidence of FIV infection for up to 18 weeks postchallenge. 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% VDDTC significantly (P=0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIVBangston-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 dual-function anti-HIV microbicide for sexually active women.