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

跨性别男性男性化性别肯定激素治疗对子宫颈粘膜组织离体 HIV-1 感染易感性的影响

• 批准号: 10748946
• 负责人: JOHN Christopher KAPPES
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748946
• 关键词: Adult; Affect; Androgens; Anti-Inflammatory Agents; Applications Grants; Bacterial Vaginosis; Biological; Cells; Cervical; Characteristics; Community Participation; Coupled; Development; Elasticity; Female; Frequencies; Future; HIV; HIV-1; Hormones; Hysterectomy; Immune response; Immunologics; Individual; Infection; Knowledge; Lactobacillus; Libido; Life Style; Masculine; Medical; Modeling; Mucous Membrane; Natural Immunity; Operative Surgical Procedures; Physiological; Population; Predisposition; Prevention strategy; Property; Reporting; Research; Research Proposals; Risk; Risk Factors; Sex Behavior; Sex Characteristics; Symptoms; T-Lymphocyte; Testosterone; Tissues; Toll-like receptors; Vagina; adaptive immunity; assigned female at birth; cell type; chemokine; cis-female; cytokine; dehydroepiandrosterone; gender affirmation; gender affirming hormone therapy; hormone therapy; immune function; innate immune function; male; steroid hormone; transgender; transgender men; transmission process; vaginal dryness; vaginal lactobacilli; vaginal microbiome

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.

项目摘要/摘要 美国大约有130万成人变性人，其中约46.7万人(约36%) 都是变性人。变性人是出生时被指定为女性，但自认为是男性的人。 变性男性可能通过接受男性激素治疗和/或从生理上从女性转变为男性 子宫切除术。变性男性社区中的那些人参与了不同的性行为和生活方式，从而 性传播感染的独特风险，特别是艾滋病毒-1。目前，人们对艾滋病毒-1的影响存在很大的认识差距 关于跨性别者，包括对睾酮治疗对艾滋病毒-1易感性的影响的有限了解 和收购。超过70%的跨性男性接受睾丸素治疗，以促进男性特征并减少 二次女性性征。接受睾酮治疗的跨性男性报告阴道干燥的症状 以及弹性丧失，这会增加粘膜组织的断裂，从而增加感染HIV-1的风险 变性人中的传播。接受睾丸素治疗至少一年的跨性男性显著减少 组成阴道微生物群的乳杆菌水平，与细菌性阴道病相关，因此 增加了艾滋病毒传播的风险。和其他雄激素一样，睾酮是一种类固醇激素，它与 许多不同的细胞类型，通过其对Toll样蛋白的影响，广泛地影响先天和获得性免疫 受体、免疫反应细胞、促炎和抗炎细胞因子。睾丸素具有广泛的 对适应性和先天免疫功能的影响，并以动态的、通常是相互对抗的方式起作用 雄激素，特别是脱氢表雄酮(DHEA)，调节免疫的发育和功能 反应细胞。这项研究提案的中心假设是睾丸素改变细胞和 宫颈粘膜中影响HIV-1感染易感性的免疫反应。审问这件事 假设，我们建议描述宫颈粘膜的某些细胞和先天免疫特性。 从接受性别肯定男性化治疗的变性人身上获得的组织，并接受了 医学上建议的子宫切除术，并将这些发现与组织对HIV-1感染的易感性相关，例如 活着。我们期望确定宫颈粘膜中与睾酮治疗相关的特定变化。 并改变了对HIV-1感染的易感性。如果成功，我们的发现将为未来提供新的基础 假设驱动的研究重点是变性人男性的艾滋病毒-1预防战略。这项研究 在这份R21拨款申请中提出的建议是以以下具体目标为指导的：1.确定 睾酮对宫颈组织对HIV-1感染易感性和T淋巴细胞数量的影响； 2.检测睾酮治疗对宫颈组织细胞因子和趋化因子表达的影响。