The effects of masculinizing gender-affirming hormone therapy for transgender men on susceptibility to HIV-1 infection modelled ex vivo in cervical mucosal tissue

项目总结/摘要 美国大约有130万变性成年人，其中约467，000人（约36%） 是变性人跨性别男性是指出生时被指定为女性但被认定为男性的人。 跨性别男性可以通过接受男性化激素治疗和/或 子宫切除术跨性别男性社区的人参与了各种各样的性行为和生活方式， 对性传播疾病特别是HIV-1有独特的风险。目前，对HIV-1影响的认识存在重大差距 对跨性别男性的影响，包括对睾酮治疗对HIV-1易感性的影响的有限了解 和收购。超过70%的跨性别男性接受睾丸激素，以促进男性特征， 女性的第二性特征接受睾酮治疗的跨性别男性报告阴道干燥的症状 以及弹性的丧失，这会增加粘膜组织的破裂，从而增加感染HIV-1的风险 在跨性别者中传播用睾丸激素治疗至少一年的跨性别男性明显减少了 包括阴道微生物组的乳酸杆菌的水平，其与细菌性阴道病相关，因此 增加艾滋病毒传播的风险。像其他雄激素一样，睾酮是一种类固醇激素， 许多不同的细胞类型，通过其对Toll样细胞的作用广泛影响先天性和适应性免疫。 受体、免疫应答细胞以及促炎和抗炎细胞因子。Tehran具有广泛的 对适应性和先天性免疫功能的影响，并以动态和经常拮抗的方式与其他免疫系统相互作用。 雄激素，特别是脱氢表雄酮（DHEA），调节免疫系统的发育和功能， 反应细胞这项研究建议的中心假设是，睾丸激素改变了细胞和 宫颈粘膜的免疫反应影响对HIV-1感染的易感性。审问这个 假设，我们提出了宫颈粘膜的某些细胞和先天免疫特性的特点， 从接受性别肯定男性化治疗的变性男性获得的组织， 医学上有指征的直肠切除术，并将这些发现与组织对HIV-1感染的易感性联系起来， vivo.我们期望确定与睾酮治疗相关的宫颈粘膜的特异性改变 改变了对HIV-1感染的易感性。如果成功，我们的发现将为未来的研究提供新的基础。 假设驱动的研究侧重于变性男子的艾滋病毒-1预防战略。研究 在这个R21赠款申请中提出的是由以下具体目标指导：1。确定影响 睾酮对宫颈移植组织对HIV-1感染和T淋巴细胞群体的易感性; 和2.确定睾酮治疗对宫颈组织中细胞因子和趋化因子表达的影响。

PROJECT SUMMARY/ABSTRACT There are approximately 1.3 million transgender adults in the US, and about 467,000 of these individuals (~36%) are transgender men. Transgender men are individuals who were assigned female at birth but identify as male. Trans men may transition physiologically from female to male by receiving masculinizing hormone therapy and/or hysterectomy. Those in the trans male community participate in diverse sexual behaviors and lifestyles resulting in unique risks to STIs, especially HIV-1. Currently, there is a significant knowledge gap of the impact of HIV-1 on trans men, including limited knowledge regarding the effects of testosterone therapy on HIV-1 susceptibility and acquisition. Over 70% of trans men receive testosterone to promote masculine characteristics and reduce secondary female sex characteristics. Trans men treated with testosterone report symptoms of vaginal dryness and loss of elasticity, which increase mucosal tissue breaks, which contribute to increased risk of HIV-1 transmission in trans men. Trans men treated with testosterone for at least one year have significantly reduced levels of Lactobacillus comprising the vaginal microbiome, which correlates with bacterial vaginosis, and thus increased risk of HIV transmission. Like other androgens, testosterone is a steroid hormone that interacts with many different cell types, broadly affecting both innate and adaptive immunity through its effect on toll-like receptors, immune-response cells, and pro- and anti-inflammatory cytokines. Testosterone has broad-ranging effects on adaptive and innate immune functions and acts in a dynamic and often antagonistic manner with other androgens, particularly dehydroepiandrosterone (DHEA), to modulate the development and function of immune response cells. The central HYPOTHESIS of this research proposal is that testosterone alters cellular and immunologic responses in the cervical mucosa that affect susceptibility to HIV-1 infection. To interrogate this hypothesis, we propose to characterize certain cellular and innate immunologic properties of cervical mucosal tissue obtained from transgender men receiving gender-affirming masculinizing therapy, and undergoing medically indicated hysterectomies, and to correlate these findings to tissue susceptibility to HIV-1 infection ex vivo. We anticipate identifying specific alterations in the cervical mucosa that correlate with testosterone therapy and altered susceptibility to HIV-1 infection. If successful, our findings will provide new underpinnings for future hypothesis-driven research focused on HIV-1 prevention strategies for transgender men. The research proposed in this R21 grant application is guided by the following SPECIFIC AIMS: 1. Determine the effects of testosterone on the susceptibility of cervical explant tissue to HIV-1 infection and populations of T lymphocytes; and 2. Determine the effects of testosterone treatment on cytokine and chemokine expression in cervical tissue.