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：
10162920
负责人：
Mauricio de Aguiar Martins
金额：
$ 27.26万
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 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162920
关键词：
AIDS prevention AIDS/HIV problem Address Adult Affect Anal Sex Animals Anti-Retroviral Agents Antibodies Binding Biological 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 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/艾滋病在社会边缘猖獗，教育程度低、住房不稳定和贫困加剧人们对艾滋病毒的脆弱性。没有人比跨性别者更容易受到这些社会不公正的影响。一个典型的例子是跨性别女性（TGW）——出生时被指定为男性但表达他们的性别属于女性范围。遗憾的是，TGW 是美国艾滋病毒流行最集中的地区之一。全球范围内，全球总体患病率为 19%，感染艾滋病毒的几率比非跨性别者高 49 倍成年人。 TGW 性别肯定的一个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 引发的女性生理特征已被广泛证实，关于 FHT 对 TGW 的免疫学影响知之甚少。值得注意的是，雌二醇可以调节通过多种方式调节免疫反应，包括上调 CD4+ T 细胞上的 CCR5 表达。自从激活以来 CCR5+ CD4+ T 细胞对 HIV 感染高度敏感，更好地了解 FHT 如何影响 HIV 感染男性免疫系统可能为如何预防 TGW 中的 HIV 感染提供新的见解。对此，这里我们将在非人类灵长类动物中建立 FHT 模型，以前瞻性地解决有关 FHT 影响的两个知识差距对男性免疫系统的影响。 1) FHT 是否会增加体内 HIV 易感 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来评估记忆CD4+青少年的频率和表型接受 FHT（第 1 组）或安慰剂（第 2 组）的雄性恒河猴的血液和肠道活检中。经过通过比较第 1 组和第 2 组动物之间的活化 CD4+ T 细胞水平，该分析将揭示 FHT 是否调节生物学男性中 HIV 易感性的一个关键标志。 2）FHT是否干扰腺相关病毒（AAV}载体免疫预防？考虑到TGW感染HIV的高风险，他们将从 AAV 介导的免疫球蛋白递送中获益匪浅，因为这种方法可以提供持久的一次性给药后产生抗HIV免疫力。事实上，单剂量的 AAV 载体编码有效的极其广泛的 HIV 进入抑制剂 eCD4-lg 导致 eCD4-lg 的持续表达和保护对抗恒河猴中严格的免疫缺陷病毒挑战。然而，鉴于雌二醇的免疫增强特性，FHT 可能通过以下方式破坏 TGW 中 AAV 驱动的 eCD4-Ig 表达放大宿主抗药物抗体 (ADA) - AAV 生物制剂递送的主要限制因素。为了解决这个问题有可能，第 1 组和第 2 组的所有动物将在 FHT 或安慰剂 6 个月后接种 AAV/eCD4-lg 治疗。然后，我们将比较他们的 eCD4-lg 和 ADA 血清水平，以确定 FHT 对 AAV 介导的男性 eCD4-lg 递送的影响。最终，这里提出的实验将开始揭示如何 FHT 可以影响 HIV 易感性和 TGW 免疫干预的结果。