A nonhuman primate model to study the immunological effects of feminizing hormone therapy in transgender women

艾滋病毒/艾滋病在社会边缘蓬勃发展，那里的教育程度低，住房不稳定，贫困加剧。 人们对艾滋病毒的脆弱性。没有人比变性人受到这些社会不公正的影响更大。 变性人女性(TGW)就是一个很好的例子--出生时被指定为男性，但 她们的性别沿着女性的光谱。可悲的是，TGW有一些最集中的艾滋病毒流行在 全球共患病率为19%，感染艾滋病毒的几率比非变性人高49倍 成年人。TGW性别肯定的一个关键部分是女性化激素治疗(FHT)，其中 主要药物是雌激素。尽管由FHT引发的女性身体特征已经确立， 关于FHT在TGW中的免疫学作用，人们知之甚少。值得注意的是，雌二醇可以调节 多种方式的免疫反应，包括上调CD4+T细胞上CCR5的表达。自激活以来 CCR5+CD4+T细胞对HIV感染具有高度的容许性，更好地了解FHT如何影响 男性免疫系统可能为如何在TGW预防HIV感染提供新的见解。在这方面，这里 我们将在非人类灵长类动物中模拟fht，以前瞻性地解决关于fht影响的两个知识空白。 对男性免疫系统的影响。1)FHT是否能增加体内对HIV敏感的CD4+T细胞的利用率？至 回答这个问题，我们将使用流式细胞术来评估记忆CD4+青少年的频率和表型 在接受FHT(组1)或安慰剂(组2)的雄性恒河猴的血液和肠道活检中。通过 比较第一组和第二组动物的激活的CD4+T细胞的水平，这一分析将揭示 FHT是否调节了生物男性中艾滋病毒易感性的一个关键标志。2)FHT是否干扰 腺相关病毒载体免疫预防？考虑到TGW感染艾滋病毒的高风险，他们 将从AAV介导的免疫球蛋白传递中受益匪浅，因为这种方法可以提供持久的 一次服药后抗HIV免疫。事实上，单剂量的AAV载体编码有效的 和极其广泛的HIV进入抑制剂eCD4-lg导致eCD4-lg的持续表达和保护 在恒河猴身上对抗严格的免疫缺陷病毒挑战。然而，鉴于 雌二醇的免疫增强作用可能通过抑制AAV诱导的TGW中eCD4-lg的表达 放大宿主抗药物抗体(ADA)--AAV运送生物制品的一个主要限制因素。要解决这个问题 有可能，第1组和第2组的所有动物将在服用FHT或安慰剂6个月后接种AAV/eCD4-LG 心理治疗。然后，我们将比较他们血清中eCD4-lg和ADAs的水平，以确定Fht对AAV介导的男性eCD4-lg传递的影响。最终，这里提出的实验将开始揭示如何 FHT可影响TGW中HIV的易感性和免疫干预的结果。

HIV/AIDS thrives in the margins of society, where low education, unstable housing, and poverty heighten people's vulnerability to HIV. No population is more affected by these social injustices than transgender persons. A case in point is transgender women (TGW}-individuals who were assigned a male sex at birth but express their gender along a feminine spectrum. Sadly, TGW have some of the highest concentrated HIV epidemics in the world, with a pooled global prevalence of 19% and a 49-fold higher odds ratio of acquiring HIV than non-transgender adults. A key part of gender affirmation in TGW is feminizing hormone therapy (FHT), of which the main drug is the hormone estradiol. Although the physical female traits triggered by FHT are well established, less is known about the immunological effects of FHT in TGW. It is noteworthy that estradiol can modulate immune responses in many ways, including by upregulating CCR5 expression on CD4+ T-cells. Since activated CCR5+ CD4+ T-cells are highly permissive to HIV infection, a better understanding of how FHT impacts the male immune system may provide new insights into how to prevent HIV infection in TGW. In this regard, here we will model FHT in nonhuman primates to prospectively address two knowledge gaps about the impact of FHT on the male immune system. 1) Does FHT increase the availability of HIV-susceptible CD4+ T-cells in vivo? To answer this question, we will use flow cytometry to assess the frequency and phenotype of memory CD4+ Teens in blood and gut biopsies from male rhesus macaques receiving FHT (Group 1) or placebo (Group 2). By comparing the levels of activated CD4+ T-cells between animals in Groups 1 and 2, this analysis will reveal whether FHT modulates a crucial marker of HIV susceptibility in biological males. 2) Does FHT interfere with adeno-associated virus (AAV}-vectored immunoprophylaxis? Considering TGW's high risk of acquiring HIV, they stand to benefit greatly from AAV-mediated delivery of immunoglobulins as this approach can provide durable anti-HIV immunity after a one-time administration. Indeed, a single dose of an AAV vector encoding the potent and extremely broad HIV entry inhibitor eCD4-lg resulted in persistent expression of eCD4-lg and protection against stringent immunodeficiency virus challenges in rhesus macaques. However, given the immunoenhancing properties of estradiol, FHT may undermine AAV-driven eCD4-lg expression in TGW by amplifying host anti-drug antibodies (ADAs}-a major limiting factor for AAV delivery of biologics. To address this possibility, all animals in Groups 1 and 2 will be inoculated with AAV/eCD4-lg after 6 months of FHT or placebo therapy. We will then compare their serum levels of eCD4-lg and ADAs to determine the impact of FHT on AAV-mediated delivery of eCD4-lg in males. Ultimately, the experiments proposed here will begin to uncover how FHT can affect HIV susceptibility and the outcome of immune interventions in TGW.