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

PrEP药物对女性生殖器HIV感染及妇女生殖健康的影响

• 批准号: 10703238
• 负责人: Ashley F George
• 金额: $ 12.66万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10703238
• 关键词: 3-Dimensional; AIDS prevention; Academia; Adherence; Adverse effects; Affect; Age; Anatomy; Antibodies; Award; Biological; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; California; Cells; Coculture Techniques; Coitus; Communicable Diseases; Complex; Dapivirine; Data; Decidual Cell Reactions; Development; Development Plans; Effector Cell; Endocervix; Endometrial; Endometrium; Environment; Exocervix; Female; Female genitalia; Fertility; Fibroblasts; Gastrointestinal tract structure; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; Health; Heterosexuals; Immune; Immunophenotyping; Impairment; In Vitro; Infection; Infection prevention; Inflammation; Integrase Inhibitors; Interferons; Invaded; Knowledge; Life; Maintenance; Methods; Modeling; Monitor; Mucous Membrane; Mus; Natural Killer Cells; Organoids; Ovarian hormone; Periodicity; Pharmaceutical Preparations; Phenotype; Physiological; Play; Predisposition; Pregnancy; Pregnancy Complications; Process; Progesterone; Public Health; Regimen; Reporting; Reproductive Health; Reproductive Immunology; Reproductive Process; Reproductive Tract Infections; Research; Research Personnel; Research Proposals; Resources; Reverse Transcriptase Inhibitors; Risk; Role; San Francisco; Seminal fluid; Signal Transduction; Socioeconomic Factors; Spiral Artery of the Endometrium; Surface; System; Tenofovir; Testing; Training; Universities; Uterus; Viral; Woman; Women' s Health; aged; career; career development; cell type; design; experimental study; fetal; immune activation; in vivo; infection rate; inflammatory milieu; inhibitor; insight; men who have sex with men; microbiome composition; mouse model; multiple omics; natural Blastocyst Implantation; peripheral blood; permissiveness; pre-exposure prophylaxis; prevent; prophylactic; reproductive; reproductive system disorder; reproductive tract; sexual HIV transmission; single-cell RNA sequencing; tissue culture; tool; transcriptome; transmission process; trophoblast; vaginal microbiome; virology; young woman

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.

项目总结 在世界范围内，年轻育龄妇女占新的艾滋病毒感染的大多数，这往往是 通过异性性交传播的。暴露前预防(PrEP)药物一直高度 有效地预防男男性行为者(MSM)中的艾滋病毒传播。然而，PrEP在 女性变得更加多变，这归因于社会原因，低忠诚度和应得的 女性生殖道(FRT)相对于胃肠道(GI)的生物学和解剖学差异 一条小路。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 提高艾滋病毒感染率。这些同样的因素也会降低PrEP药物的抗艾滋病毒活性。同样多的人 有艾滋病毒风险的妇女是育龄妇女，同样重要的是确定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。准备 也被证明可以在粘膜组织中诱导干扰素信号，这可能会影响FRT T的功能 和自然杀伤(NK)细胞。值得注意的是，T和NK细胞是在病毒防御中发挥关键作用的效应细胞 还有怀孕。这些观察结果表明，在FRT微环境中对PrEP有了更好的理解， 以及PrEP对妊娠的潜在不良影响是必要的。我正在追求K99奖，以获得 进一步培训以满足我的长期职业目标：成为一名进行研究的独立调查员 关于影响妇女的传染病和生殖障碍。格莱斯顿学院的环境和 加州大学旧金山分校是特例，将提供必要的资源 圆满完成我的职业发展计划，实现我的职业目标。这项研究的目的是 建议确定FRT的环境如何影响PrEP疗效，反过来PrEP如何影响PrEP 会影响FRT从而影响生育能力。我的假设是，FRT粘膜因素对抗HIV产生不利影响 一些但不是所有的PrEP方案可以扰乱对妊娠重要的FRT过程。 在目标1中，我将使用FRT感染模型和细胞周期图来确定PrEP的活性是如何受到 FRT黏膜的环境。在目标2中，我将使用体外组织培养和有机模型，以及在 活体小鼠模型，以确定PrEP药物如何影响怀孕和对怀孕重要的过程 建立和维护。在目标3中，我将使用多组学方法来表征来自 接受或不接受PrEP的HIV血清阴性育龄妇女的FRT，以评估其程度 PREP改变了这些细胞的表型。识别易感人群感染HIV的机制 在PrEP浓度低于最佳浓度的情况下，FRT中的细胞(这种情况在FRT中比在 胃肠道)对于发展有效的PrEP将是至关重要的，年轻女性可以安全地使用而不必担心 关于潜在的怀孕并发症。这可能会极大地降低生殖器的传播率- 妇女老龄化，并对全球公共卫生产生重大影响。