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.

为了在美国和全世界结束这种流行病，必须采取多种方法相结合的方式 实施的措施包括早期发现、预防战略、更高的治疗效率和可及性， 外展，希望还有疫苗和治愈方法。潜伏的HIV感染细胞的存在 构成了寻找艾滋病毒治疗方法的主要障碍。潜伏感染与检测不到有关 病毒基因的表达水平，似乎是非细胞病变的。几种治疗干预措施 潜伏的艾滋病毒正在调查中。其中，“电击和杀死”策略已经在人体上进行了临床试验 艾滋病毒携带者(PLWH)。制定这些和其他干预措施以遏制这一流行病必须考虑 不同的种群以及这些策略的有效性是否在特定的生物学功能上有所不同 各种因素。性激素，包括雌激素、睾酮和黄体酮，是性激素的关键媒介。 发展。性激素受体除了在性发育中起主要作用外，还存在于免疫系统中。 并可影响艾滋病毒感染、艾滋病毒转录以及免疫细胞功能。然而，我们正在 限制了我们对性激素是否以及如何影响治疗策略的理解。这一点在 制定旨在治愈包括妇女和妇女在内的妇女和妇女的艾滋病毒的治疗干预措施 变性人。女性占全球所有感染者和变性人的一半以上，这占到了 在美国，高达0.6%的育龄成年人感染艾滋病毒的风险大约高出49倍 感染。这些人群将从治疗方法中受益匪浅。然而，性激素是否 在变性过程中使用的激素替代疗法可能会干扰治愈 策略是完全未知的。 在目标1中，我们建议使用HIV潜伏期的原代细胞模型来解决性激素作为 在变性人的激素替代治疗中使用的抗雄激素可能会影响 建立HIV潜伏期。我们还将评估性激素和抗雄激素是否会影响 一组潜伏期反转剂(LRA)的活性，包括用于根除艾滋病毒的临床试验的LRA。 在目标2中，我们打算评估目前在临床上使用的Toll样受体激动剂的活性 根除艾滋病毒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会影响NK细胞的活性。NK细胞是先天免疫的一部分。 免疫系统，并在控制艾滋病毒感染方面发挥重要作用。性激素已经被证明可以 不利影响NK的抗肿瘤活性。然而，关于性激素是否会影响这一问题，我们知之甚少。 它们的抗艾滋病毒活性。我们的研究将在设计战略目标的时候产生特别的兴趣 旨在消除包括妇女和变性人在内的不同PLWH中的艾滋病毒潜在储蓄者，并将 告知性激素在当前和未来的艾滋病毒治疗方法中可能发挥的作用。