*Departments of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine, Yeshiva University, New York, NY; †University of Pittsburgh, Pittsburgh, PA; ‡Magee-Womens Research Institute, Pittsburgh, PA; §University of Washington, Seattle, WA; ‖Fred Hutchinson Cancer Research Center, Seattle, WA; and ¶Johns Hopkins University, Baltimore, MD.
J Acquir Immune Defic Syndr. 2014 May 1;66(1):65-73. doi: 10.1097/QAI.0000000000000110.
Surrogate markers of HIV-1 pre-exposure prophylaxis and microbicide efficacy are needed. One potential surrogate is the antiviral activity in cervicovaginal lavage (CVL) after exposure to candidate products. We measured CVL antiviral activity in women using oral or vaginal tenofovir-based pre-exposure prophylaxis and correlated activity with drug and immune mediator levels.
Inhibitory activity against HIV-1 and herpes simplex virus (HSV)-2 and concentrations of interleukin (IL)-1β, IL-6, IL-8, interferon-γ, induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, MIP-3a, lactoferrin, secretory leukocyte protease inhibitor, and defensins were measured in CVL obtained from 60 women at baseline and after 6 weeks of a randomized sequence of oral and topical tenofovir. CVL tenofovir concentrations were measured by mass spectrometry.
The number of women with CVL anti-HIV activity ≥ 90% increased significantly from 5.0% at baseline to 89.1% after daily use of 1% tenofovir gel (relative risk = 17.85, P < 0.001), but there was no increase after daily oral tenofovir. The CVL anti-HIV activity correlated with drug levels (Spearman correlation coefficient 0.64 after tenofovir gel; P < 0.001) but not with the concentrations of mucosal immune mediators. No increase in CVL anti-HSV activity was observed after either drug regimen, an observation consistent with the higher concentrations of tenofovir needed to inhibit HSV-2 infection. The CVL anti-HSV activity correlated with lactoferrin, defensins, IP-10, IL-8, and detectable levels of MIP-1α but not with drug levels.
CVL may provide a surrogate for local but not systemic drug efficacy and a tool to better understand mucosal factors that modulate antiviral activity in genital tract secretions.
需要寻找 HIV-1 暴露前预防和杀微生物剂疗效的替代标志物。一种潜在的替代标志物是候选产品暴露后宫颈阴道灌洗液（CVL）中的抗病毒活性。我们使用口服或阴道给予的基于替诺福韦的暴露前预防药物来测量女性 CVL 的抗病毒活性，并将活性与药物和免疫介质水平相关联。
我们测量了 60 名女性在基线和口服及局部使用替诺福韦 6 周后的 CVL 对 HIV-1 和单纯疱疹病毒（HSV）-2 的抑制活性以及白细胞介素（IL）-1β、IL-6、IL-8、干扰素-γ、诱导蛋白 10（IP-10）、巨噬细胞炎性蛋白（MIP）-1α、MIP-3α、乳铁蛋白、分泌型白细胞蛋白酶抑制剂和防御素的浓度。CVL 中的替诺福韦浓度通过质谱法测量。
使用 1%替诺福韦凝胶每日一次时，CVL 抗 HIV 活性≥90%的女性人数从基线时的 5.0%显著增加到 89.1%（相对风险=17.85，P<0.001），但口服替诺福韦每日一次时没有增加。CVL 抗 HIV 活性与药物水平相关（替诺福韦凝胶后 Spearman 相关系数为 0.64；P<0.001），但与黏膜免疫介质的浓度无关。两种药物方案后，CVL 抗 HSV 活性均无增加，这一观察结果与抑制 HSV-2 感染所需的更高浓度的替诺福韦一致。CVL 抗 HSV 活性与乳铁蛋白、防御素、IP-10、IL-8 和可检测到的 MIP-1α浓度相关，但与药物水平无关。
CVL 可能提供局部而非全身药物疗效的替代标志物，以及更好地理解调节生殖道分泌物中抗病毒活性的黏膜因素的工具。
