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

用于研究跨性别女性女性化激素治疗的免疫学影响的非人类灵长类动物模型

基本信息

批准号：
10307630
负责人：
Mauricio de Aguiar Martins
金额：
$ 18.04万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307630
关键词：
AIDS prevention AIDS/HIV problem Address Adult Affect Anal Sex Animals Anti-Retroviral Agents Antibodies Binding Biological Biological Products Biopsy Birth Blood CCR5 gene CD4 Positive T Lymphocytes CXCR4 gene Cells Clinical Research Communities Containment Data Dependovirus Discrimination Dose Drug or chemical Tissue Distribution Education Employment Enrollment Epidemic Estradiol Exposure to Female Feminine Feminization Flow Cytometry Frequencies Fright Future Gender Gut Mucosa HIV HIV Entry Inhibitors HIV Infections High Risk Woman Hormones Immune Immune response Immune system Immunity Immunoglobulin G Immunoglobulins Immunologic Deficiency Syndromes Immunologics Incidence Income Individual Infection Kinetics Knowledge Link Macaca mulatta Mediating Memory Methods Modeling Monkeys Mucous Membrane Odds Ratio Outcome Persons Pharmaceutical Preparations Pharmacodynamics Phenotype Placebos Population Poverty Predisposition Prevalence Primate Lentiviruses Property Regimen Reporting Research Design SIV Sampling Serum Sexual Reassignment Shapes Societies Sum T-Cell Development Teenagers Time Tissues Up-Regulation Ursidae Family Virus Vulnerable Populations Work adeno-associated viral vector antiviral immunity env Gene Products experimental study fighting gene therapy high risk behavior hormone therapy housing instability immunological intervention immunoprophylaxis in vivo insight male memory CD4 T lymphocyte nonhuman primate peptidomimetics placebo group pre-exposure prophylaxis prevent prophylactic prospective receptor rectal sex simian human immunodeficiency virus social social stigma tool trait transgender transgender women transmission process vector virtual

项目摘要

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.

艾滋病毒/艾滋病在社会边缘繁荣发展，那里的低教育，不稳定的住房和贫困增强人们对艾滋病毒的脆弱性。没有人群比跨性别者更受这些社会不公的影响。一个典型的例子是变性妇女（TGW} - 个人在出生时被分配的男性但表达他们的性别沿着女性谱系。可悲的是，TGW在某些最高浓度的HIV流行病中世界，全球流行率为19％，获得艾滋病毒的比值比高49倍成年人。 TGW中性别肯定的关键部分是女性化激素疗法（FHT），其中主要药物是激素雌二醇。尽管FHT触发的身体特征已经很好，但对FHT在TGW中的免疫学影响知之甚少。值得注意的是，雌二醇可以调节免疫反应在许多方面，包括通过上调CCR5在CD4+ T细胞上的表达。自激活以来 CCR5+ CD4+ T细胞高度允许HIV感染，更好地理解FHT如何影响男性免疫系统可能会提供有关如何预防TGW中艾滋病毒感染的新见解。在这方面，这里我们将在非人类灵长类动物中对FHT进行建模，以期待有关FHT影响的两个知识差距在男性免疫系统上。 1）FHT是否会增加体内HIV敏感CD4+ T细胞的可用性？到回答这个问题，我们将使用流式细胞术评估记忆CD4+青少年的频率和表型在接受FHT（第1组）或安慰剂（第2组）的雄性恒河猕猴的血液和肠击活检中。经过比较第1组和第2组动物之间激活的CD4+ T细胞的水平，该分析将显示 FHT是否调节生物雄性中HIV敏感性的关键标记。 2）FHT干扰腺相关病毒（AAV} - 载体免疫预防？考虑到TGW获得HIV的高风险，它们该方法可以从AAV介导的免疫球蛋白的传递中受益匪浅，因为这种方法可以提供耐用一次性给药后的抗HIV免疫。实际上，单剂量编码有效的AAV矢量并且非常广泛的HIV进入抑制剂ECD4-LG导致ECD4-LG的持续表达和保护针对恒河猕猴中严格的免疫缺陷病毒挑战。但是，给定雌二醇的免疫融合特性，FHT可能会破坏TGW中AAV驱动的ECD4-LG表达放大宿主抗药物抗体（ADAS} - AAV递送生物制剂的主要限制因素。可能性，第1组和第2组中的所有动物将在6个月或安慰剂后接种AAV/ECD4-LG 治疗。然后，我们将比较它们的ECD4-LG和ADA的血清水平，以确定FHT对AAV介导的ECD4-LG在男性中的影响。最终，这里提出的实验将开始揭示如何 FHT会影响HIV敏感性和TGW中免疫干预的结果。