权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10591742
负责人：
Mauricio de Aguiar Martins
金额：
$ 2.41万
依托单位：
UNIVERSITY OF 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/10591742
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.

艾滋病在教育水平低、住房不稳定和贫困加剧的社会边缘地区肆虐