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: 10548694
• 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/10548694
• 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; HIV Seronegativity; Health; Heterosexuals; Immune; Immunophenotyping; Impairment; In Vitro; Infection; Infection prevention; Inflammation; Institutes; Integrase Inhibitors; Interferons; Knowledge; Lead; 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; 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.

项目概要 在世界范围内，年轻育龄妇女占新发艾滋病毒感染者的大多数，这往往是 通过异性性交传播的风险很高。 PrEP 可有效预防男男性行为者 (MSM) 中的 HIV 传播，但 PrEP 的功效却有限。 女性的差异性更大，这归因于社会原因、依从性低以及由于 女性生殖道 (FRT) 相对于胃肠道 (GI) 的生物学和解剖学差异 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 这些因素也会增加 HIV 感染率，从而降低 PrEP 药物的抗 HIV 活性。 面临艾滋病毒风险的女性处于育龄期，因此确定 PrEP 可能达到的程度也很重要。 事实上，据报道，一些 PrEP 药物会损害怀孕所必需的过程。 还被证明可以在粘膜组织中引发干扰素信号传导，从而影响 FRT T 的功能 值得注意的是，T 细胞和 NK 细胞是在病毒防御中发挥关键作用的效应细胞。 这些观察结果表明我们可以更好地了解 FRT 微环境中的 PrEP， 以及 PrEP 对怀孕的潜在不利影响，我正在争取 K99 奖才能获得。 进一步培训以实现我的长期职业目标：成为一名独立调查员进行研究 格拉德斯通研究所和影响妇女的传染病和生殖障碍的环境。 加州大学旧金山分校非常出色，将为您提供必要的资源 顺利完成我的职业发展计划并实现我的职业目标。 建议是确定 FRT 的环境如何影响 PrEP 功效，以及反过来如何影响 PrEP 可以影响 FRT 从而影响生育能力 我的假设是 FRT 粘膜因素会对抗 HIV 产生不利影响。 PrEP 的活性，并且一些但不是所有的 PrEP 方案会破坏对怀孕很重要的 FRT 过程。 在目标 1 中，我将使用 FRT 感染模型和 CyTOF 来确定 PrEP 的活性如何受到感染的影响。 在目标 2 中，我将使用离体组织培养和类器官模型。 体内小鼠模型，以确定 PrEP 药物如何影响妊娠以及对妊娠重要的过程 在目标 3 中，我将使用多组学方法来表征 T 和 NK 细胞。 对正在接受或未接受 PrEP 的 HIV 血清阴性育龄妇女进行 FRT，以评估其程度 PrEP 改变这些细胞的表型，确定 HIV 感染易感性的机制。 在 PrEP 浓度不理想的情况下，FRT 中的细胞（这在 FRT 中比在 胃肠道）对于开发有效的 PrEP 至关重要，年轻女性可以放心地安全使用 关于潜在的妊娠并发症，这可能会大大降低生殖系统的传播率。 老龄化妇女并对全球公共卫生产生重大影响。