Hormonal control of HIV latency

HIV潜伏期的激素控制

• 批准号: 10201490
• 负责人: Alberto Bosque
• 金额: $ 39.88万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-24 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201490
• 关键词: Address; Adult; Affect; Age; Agonist; Androgen Antagonists; Basic Science; Biological; Biological Factors; Biology; CD4 Positive T Lymphocytes; Cell model; Cell physiology; Cells; Clinical; Clinical Trials; Development; Disease; Disease Progression; Dose; Early Diagnosis; Effector Cell; Epidemic; Estradiol; Estrogens; Female; Funding Opportunities; Future; Gender; Gene Expression; Generations; Genetic Transcription; Gonadal Steroid Hormones; HIV; HIV Antibodies; HIV Infections; Health; Hormonal; Hormone Receptor; Hormone replacement therapy; Immune; Immune system; Individual; Infection; Innate Immune System; Intervention; Investigation; Killer Cells; Knowledge; Life; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Menopause; Menstruation; Mucosal Immune Responses; Nature; Participant; Patients; Play; Population; Pregnancy; Prevention strategy; Progesterone; Property; Replacement Therapy; Research; Research Personnel; Role; Sexual Development; Sexual Reassignment; Shock; Spironolactone; Testing; Testosterone; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Transcriptional Activation; Treatment Efficacy; Vaccines; Viral; Viral Genes; Woman; antiretroviral therapy; base; cis-female; cis-male; clinically relevant; design; experience; falls; high risk; hormone regulation; immune activation; interest; latent HIV reservoir; latent infection; male; outreach; reactivation from latency; reproductive; research clinical testing; sex; therapeutic development; transgender; tumor

In order to end the epidemic in the US and worldwide a combination of approaches must be implemented that include early detection, prevention strategies, higher treatment efficacy and accessibility, outreach, and hopefully a vaccine and a cure. The existence of a latent reservoir of HIV-infected cells constitutes the major impediment towards finding an HIV cure. Latent infection is associated with undetectable levels of viral gene expression and appears to be non-cytopathic. Several therapeutic interventions against latent HIV are under investigation. Among them, ‘shock and kill’ strategies have reached clinical trials in people living with HIV (PLWH). The development of these and other interventions to curb the epidemic has to consider different populations and whether the efficacy of these strategies may vary in function of specific biological factors. Sex hormones, including estrogen, testosterone and progesterone, are critical mediators of sexual development. Besides their main role in sexual development, sex hormone receptors are present in immune cells and can influence HIV infection, HIV transcription as well as immune cell function. However, we are limited in our understanding whether and how sex hormones could influence cure strategies. This is crucial in the development of therapeutic interventions aimed towards an HIV cure in PLWH, including women and transgender. Women represent more than half of all the infections worldwide and transgender, which account for up to 0.6% of reproductive age adults in the US, are at approximately 49-fold higher risk of acquiring HIV infection. These populations will tremendously benefit from cure approaches. However, whether sex hormones and hormonal replacement therapies used during gender reassignment could potentially interfere with cure strategies is completely unknown. In Aim 1, we proposed to use a primary cell model of HIV latency to address whether sex hormones as well as antiandrogens used in hormonal replacement therapy for transgender individuals could influence the establishment of HIV latency. We will also evaluate whether sex hormones and antiandrogens influence the activity of a panel of latency-reversing agents (LRAs), including LRAs used in clinical trials for HIV eradication. In Aim 2, we intend to evaluate whether the activity of toll-like receptors (TLRs) agonists currently under clinical trials to eradicate HIV could be influenced by sex hormones and antiandrogens. Finally, in Aim 3 we will explore whether sex hormones and antiandrogens influence NK cell activity. NK cells are part of the innate immune system and play an important role in controlling HIV infection. Sex hormones have been shown to detrimentally affect NK anti-tumoral activity. However, less is known on whether sex hormones could influence their anti-HIV activity. Our studies will be of particular interests at the time of designing strategies aimed towards eliminating the HIV latent reservoir in different PLWH, including women and transgender, and will inform of the role that sex hormones could play in current and future HIV cure approaches.

为了结束美国和全球的流行病，一定的方法必须是 实施包括早期检测，预防策略，更高的治疗效率和可及性， 推广，希望是一种疫苗和治愈方法。 HIV感染细胞的潜在储层的存在 构成寻找艾滋病毒治愈方法的主要障碍。潜在感染与无法检测到 病毒基因表达的水平，似乎是非环保性的。几种针对的治疗干预措施 潜在的艾滋病毒正在调查中。其中，“震惊和杀戮”策略已经进行了临床试验 与艾滋病毒（PLWH）同住。这些和其他干预措施以遏制流行病的发展必须考虑 不同的人群以及这些策略的效率是否可能在特定生物学的功能上有所不同 因素。性骑手，包括雌激素，睾丸激素和孕激素，是性的关键介体 发展。除了他们在性发展中的主要作用外，性马酮受体还存在于免疫中 细胞并可能影响HIV感染，HIV转录以及免疫细胞功能。但是，我们是 我们了解性激素是否以及如何影响治疗策略的限制。这至关重要 针对PLWH的艾滋病毒治疗的治疗干预措施的发展，包括妇女和 跨性别。妇女代表了全球所有感染和变性者的一半以上 在美国，多达0.6％的生殖年龄成年人的收购艾滋病毒风险高约49倍 感染。这些人群将从治愈方法中受益匪浅。但是，是否性恐怖 性别重新分配期间使用的激素替代疗法可能会干扰治愈 策略是完全未知的。 在AIM 1中，我们建议使用HIV潜伏期的主要细胞模型来解决性激素是否作为 以及用于跨性别个体的激素替代疗法中使用的抗雄激素可能会影响 建立艾滋病毒潜伏期。我们还将评估性激素和抗雄激素是否影响 一组延迟逆转剂（LRA）的活性，包括用于消除HIV的临床试验中的LRA。 在AIM 2中，我们打算评估目前在临床下的Toll样受体（TLR）激动剂的活性 放射素HIV的试验可能会受到性激素和抗雄激素的影响。最后，在目标3中，我们将 探索性激素和抗雄激素是否影响NK细胞活性。 NK细胞是先天的一部分 免疫系统并在控制艾滋病毒感染中发挥重要作用。性激素已被证明 不利影响NK抗肿瘤活性。但是，关于性马是否会影响的知之甚少 他们的抗HIV活性。在设计针对的策略时，我们的研究将特别有意义 旨在消除不同PLWH中的艾滋病毒潜伏水库，包括妇女和变性者，并将 告知性恐怖可以在当前和未来的艾滋病毒治疗方法中扮演的角色。