UC781 Microbicide Gel Retains Anti-HIV Activity in Cervicovaginal Lavage Fluids Collected following Twice-Daily Vaginal Application
UC781 Microbicide Gel Retains Anti-HIV Activity in Cervicovaginal Lavage Fluids Collected following Twice-Daily Vaginal Application
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DOI：
10.1128/aac.00452-12
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发表时间：
2012-07-01
影响因子：
4.9
通讯作者：
Hart, Clyde E.
中科院分区：
文献类型：
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作者：
Haaland, Richard E.;Evans-Strickfaden, Tammy;Hart, Clyde E.
有效的非核苷类逆转录酶抑制剂UC781作为一种阴道杀微生物剂凝胶制剂进行了安全性测试，用于预防HIV-1的性传播。为了研究UC781在暴露于女性生殖道后是否仍具有抗感染活性，我们对25名泰国妇女宫颈阴道灌洗液(CVL)中的UC781水平和抗病毒活性进行了体外分析，这些妇女参加了为期14天的安全性试验，每天两次使用两种浓度的UC781杀微生物剂凝胶。分别在第一次涂抹凝胶后(T-15分钟)和最后一次涂抹后8-24小时(T8-24小时)收集0.1%(n=5)、0.25%(n=15)和安慰剂(n=5)凝胶手臂中的CVL样本，并将其分为无细胞组(CVL-S)和颗粒剂(CVL-p)。由于UC781是高度疏水的，对于UC781凝胶臂，CVL-P样品中的UC781含量显著高于CVL-S样品中的UC781含量。在T8-24 h CVL-p样本中，分别有2/5和13/15样本分别从0.1%和0.25%UC781凝胶臂中采集，有效地阻断了CCR5嗜性CRF01_AE HIV-1毒株的a>；=4log(10)50%组织培养感染量(TCID50)的感染。与ARM无关，具有UC781水平的11个CVL-p样本的>；=5ug/cvl样本将传染性HIV降低了a>；=4log(10)TCID50。我们的结果表明，UC781凝胶制剂的水平和抗感染活性可能与CVL样品中的细胞或颗粒成分有关。因此，在候选杀菌剂的临床前研究中，应该对细胞和可制粒部分进行药物水平和抗感染活性的检测。
The potent nonnucleoside reverse transcriptase inhibitor UC781 has been safety tested as a vaginal microbicide gel formulation for prevention of HIV-1 sexual transmission. To investigate whether UC781 retained anti-infective activity following exposure to the female genital tract, we conducted an ex vivo analysis of the UC781 levels and antiviral activity in cervicovaginal lavage (CVL) fluids from 25 Thai women enrolled in a 14-day safety trial of twice-daily vaginal application of two concentrations of the UC781 microbicide gel. CVL samples were collected from women in the 0.1% (n = 5), 0.25% (n = 15), and placebo (n = 5) gel arms following the first application of gel (T-15 min) and 8 to 24 h after the final application (T8-24 h) and separated into cell-free (CVL-s) and pelletable (CVL-p) fractions. As UC781 is highly hydrophobic, there were significantly higher levels of UC781 in the CVL-p samples than in the CVL-s samples for the UC781 gel arms. In T8-24 h CVL-p samples, 2/5 and 13/15 samples collected from the 0.1% and 0.25% UC781 gel arms, respectively, efficiently blocked infection with a >= 4 log(10) 50% tissue culture infective dose (TCID50) of a CCR5-tropic CRF01_AE HIV-1 virus stock. Independent of the arm, the 11 CVL-p samples with UC781 levels of >= 5 mu g/CVL sample reduced infectious HIV by a >= 4 log(10) TCID50. Our results suggest that the levels and anti-infective activities of UC781 gel formulations are likely to be associated with a cellular or pelletable component in CVL samples. Therefore, cellular and pelletable fractions should be assayed for drug levels and anti-infective activity in preclinical studies of candidate microbicides.