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.

项目概要/摘要 美国大约有 130 万跨性别成年人，其中约 467,000 人（约 36%） 是跨性别男性。跨性别男性是指出生时被指定为女性但自我认同为男性的个体。 跨性别男性可以通过接受男性化激素治疗和/或在生理上从女性转变为男性 子宫切除术。跨性别男性群体中的人们参与多样化的性行为和生活方式，从而导致 性传播感染（STI）的独特风险，尤其是 HIV-1。目前，人们对 HIV-1 的影响存在重大认识差距 跨性别男性，包括关于睾酮治疗对 HIV-1 易感性影响的有限了解 和收购。超过 70% 的跨性别男性接受睾酮以提升男性特征并减少 女性第二性征。接受睾酮治疗的跨性别男性报告阴道干燥症状 和弹性丧失，这会增加粘膜组织破裂，从而增加感染 HIV-1 的风险 跨性别男性中的传播。接受睾酮治疗至少一年的跨性别男性的体重明显减少 构成阴道微生物群的乳酸菌水平，与细菌性阴道病相关，因此 艾滋病毒传播的风险增加。与其他雄激素一样，睾酮是一种类固醇激素，与 许多不同的细胞类型，通过其对 toll 样细胞的影响广泛影响先天性和适应性免疫 受体、免疫反应细胞以及促炎和抗炎细胞因子。睾丸激素具有广泛的 对适应性和先天免疫功能的影响，并以动态且经常与其他免疫功能对抗的方式发挥作用 雄激素，特别是脱氢表雄酮 (DHEA)，可调节免疫系统的发育和功能 反应细胞。该研究计划的中心假设是睾酮改变细胞和 宫颈粘膜的免疫反应影响 HIV-1 感染的易感性。来询问这个 假设，我们建议表征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并接受性别肯定男性化治疗的跨性别男性获得的组织 医学上指示的子宫切除术，并将这些发现与组织对 HIV-1 感染的易感性联系起来 体内。我们预计会发现与睾酮治疗相关的宫颈粘膜的特定变化 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关注跨性别男性的 HIV-1 预防策略。研究 本 R21 拨款申请中提出的建议以以下具体目标为指导： 1. 确定 睾酮对宫颈外植体组织对 HIV-1 感染和 T 淋巴细胞群体的易感性的影响； 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。