Effects of PrEP Drugs on Female Genital HIV Infection and Women's Reproductive Health

项目摘要 在世界范围内，年轻的育龄妇女占新感染艾滋病毒的大多数，这往往是一个严重的问题。 通过异性性交传播暴露前预防性（PrEP）药物一直受到高度重视。 有效预防艾滋病毒在男男性行为者（MSM）中传播。然而，PrEP在 妇女的变化要大得多，这是由于社会原因，坚持率低， 女性生殖道（FRT）相对于胃肠道（GI）的生物学和解剖学差异 道。许多FRT粘膜因子--包括FRT成纤维细胞、精液中的因子和炎症--可以 增加艾滋病毒感染率。这些相同的因素也会降低PrEP药物的抗HIV活性。一样多 有艾滋病毒风险的妇女处于生育年龄，确定PrEP可能在多大程度上 影响生育能力。事实上，据报道，一些PrEP药物会损害怀孕所必需的过程。PrEP 还显示在粘膜组织中引发干扰素信号传导，这可能影响FRT T的功能 自然杀伤细胞（NK）值得注意的是，T细胞和NK细胞是效应细胞，在病毒防御中起关键作用。 还有怀孕这些观察结果表明更好地理解FRT微环境中的PrEP， 以及PrEP对妊娠的潜在不良影响。我追求K99奖，以获得 进一步的培训，以满足我的长期职业目标：成为一个独立的调查员进行研究 关于影响妇女的传染病和生殖失调的报告。格莱斯顿研究所的环境， 加州大学旧金山弗朗西斯科是例外，并将提供必要的资源， 顺利完成我的职业发展计划，实现我的职业目标。本研究的目的 建议是确定FRT的环境如何影响PrEP的有效性，以及相反，PrEP如何影响PrEP的有效性。 可以影响FRT从而影响生育能力。我的假设是，FRT粘膜因子对抗HIV 一些但不是所有的PrEP方案可以破坏对怀孕重要的FRT过程。 在目标1中，我将使用FRT感染模型和CyTOF来确定PrEP的活性如何受到 FRT粘膜的环境。在目标2中，我将使用离体组织培养和类器官模型，以及 体内小鼠模型，以确定PrEP药物如何影响妊娠和妊娠重要过程 建立和维护。在目标3中，我将使用多组学方法来表征T和NK细胞， HIV血清阴性的育龄妇女接受或不接受PrEP的FRT，以评估在多大程度上 PrEP改变了这些细胞的表型。确定易感人群感染艾滋病毒的潜在机制 在次优浓度的PrEP背景下，FRT中的细胞（这在FRT中比在 胃肠道）将是至关重要的发展有效的准备，年轻妇女可以安全地使用，而不必担心 潜在的妊娠并发症这可以大大降低生殖系统的传播率- 对全球公共卫生产生重大影响。

PROJECT SUMMARY Worldwide, young reproductive age women account for the majority of new HIV infections, which is often transmitted through heterosexual intercourse. Pre-exposure prophylactic (PrEP) drugs have been highly effective in preventing HIV transmission in men who have sex with men (MSM). However, PrEP efficacy in women has been much more variable, which has been attributed to societal reasons, low adherence, and due to biological and anatomical differences of the female reproductive tract (FRT) relative to the gastrointestinal (GI) tract. A number of FRT mucosal factors – including FRT fibroblasts, factors in semen, and inflammation – can increase HIV infection rates. These same factors can also diminish the anti-HIV activity of PrEP drugs. As many women at risk of HIV are of reproductive age, it is also important to determine the extent to which PrEP may affect fertility. Indeed, some PrEP drugs have been reported to impair processes essential for pregnancy. PrEP has also been shown to elicit interferon signaling in mucosal tissues, which could affect the functions of FRT T and Natural Killer (NK) cells. Of note, T and NK cells are effector cells that play critical roles in both viral defense and pregnancy. These observations suggest a better understanding of PrEP within the FRT microenvironment, and of potential adverse effects of PrEP on pregnancy, is needed. I am pursuing the K99 Award in order to gain further training to meet my long-term career goals: to become an independent investigator conducting research on infectious diseases and reproductive disorders affecting women. The environment at Gladstone Institutes and the University of California at San Francisco are exceptional and will provide the essential resources to successfully complete my career development plan and achieve my career goals. The objective of this research proposal is to determine how the environment of the FRT can influence PrEP efficacy, and conversely how PrEP can influence the FRT to affect fertility. My hypothesis is that FRT mucosal factors adversely affect the anti-HIV activities of PrEP, and that some but not all PrEP regimens can disrupt FRT processes important for pregnancy. In Aim 1, I will use FRT infection models and CyTOF to determine how the activity of PrEP is affected by the environment of the FRT mucosa. In Aim 2, I will use ex vivo tissue culture and organoid models, as well as in vivo mouse models, to determine how PrEP drugs affect pregnancy and processes important for pregnancy establishment and maintenance. In Aim 3, I will use multi-omics approaches to characterize T and NK cells from FRT of HIV-seronegative, reproductive-age women who are on or off PrEP, in order to assess to what extent PrEP alters the phenotypes of these cells. Identifying the mechanisms underlying HIV infection of susceptible cells in FRT in the context of suboptimal concentrations of PrEP (which is more common in the FRT than in the GI tract) will be crucial for the development of effective PrEP that young women can safely use without worrying about potential pregnancy complications. This could dramatically reduce the rate of transmission in reproductive- age women and have a significant impact on global public health.