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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/艾滋病在社会边缘地区蔓延，那里教育水平低，住房不稳定，贫困加剧人们对艾滋病毒的脆弱性。没有人比变性人更受这些社会不公正的影响。一个恰当的例子是跨性别妇女（TGW）-出生时被指定为男性，但他们的性别沿着一个女性光谱。可悲的是，TGW有一些最集中的艾滋病毒流行，全球总患病率为19%，感染艾滋病毒的几率比非变性人高49倍。成年人了TGW中性别肯定的一个关键部分是女性化激素治疗（FHT），其中主要药物是雌二醇。虽然FHT引发的女性生理特征已经得到了很好的证实，关于FHT在TGW中的免疫学作用知之甚少。值得注意的是，雌二醇可以调节通过多种方式，包括通过上调CCR 5在CD 4 + T细胞上的表达，来产生免疫应答。自启动以来 CCR 5 + CD 4 + T细胞对HIV感染高度宽容，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，在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是否增加体内HIV易感性CD 4 + T细胞的可用性？到为了回答这个问题，我们将使用流式细胞术来评估记忆性CD 4+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活检中。通过比较第1组和第2组动物之间活化的CD 4 + T细胞水平，该分析将揭示 FHT是否调节了生物学上男性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感染艾滋病毒的高风险，他们因为这种方法可以提供持久免疫球蛋白递送，一次给药后的抗HIV免疫力。事实上，编码有效的重组腺病毒载体的单剂量给药可以使细胞内的细胞内的细胞增殖。和极其广泛的HIV进入抑制剂eCD 4-lg导致eCD 4-lg的持续表达和保护作用在恒河猴中对抗严格的免疫缺陷病毒攻击。但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eCD 4-lg表达：扩增宿主抗药抗体（ADA）-生物制剂的AAV递送的主要限制因素。为了解决这个可能性，第1组和第2组中的所有动物将在FHT或安慰剂治疗6个月后接种AAV/eCD 4-lg 疗法然后，我们将比较它们的eCD 4-Ig和ADA的血清水平，以确定FHT对雄性中AAV介导的eCD 4-Ig递送的影响。最终，这里提出的实验将开始揭示如何 FHT可影响TGW中的HIV易感性和免疫干预的结果。