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Hormonal control of HIV latency

HIV潜伏期的激素控制

基本信息

批准号：
10650164
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
项目类别：
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/10650164
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 Menopause Menstruation Mucosal Immune Responses Nature Participant Patients Persons 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 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

项目摘要

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.

为了在美国和世界范围内结束这一流行病，必须采取多种方法，实施包括早期发现、预防战略、更高的治疗功效和可及性的措施，希望能找到疫苗和治愈方法HIV感染细胞的潜在储存库的存在是找到艾滋病治愈方法的主要障碍。潜伏性感染与无法检测到的病毒基因表达水平，似乎是非细胞病变。几种治疗性干预措施，潜伏艾滋病毒正在调查中。其中，“休克和杀死”策略已进入人体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，不同的人群，以及这些策略的疗效是否可能在特定的生物学功能方面有所不同，因素性激素，包括雌激素、睾酮和孕酮，是性行为的关键介质。发展除了在性发育中的主要作用外，性激素受体还存在于免疫系统中。细胞，可以影响HIV感染，HIV转录以及免疫细胞功能。但我们我们对性激素是否以及如何影响治疗策略的理解有限。这一点至关重要，制定治疗干预措施，旨在治愈艾滋病毒携带者，包括妇女，变性人妇女占全世界所有感染者的一半以上，变性人占在美国，高达0.6%的育龄成年人感染艾滋病毒的风险约高出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战略是完全未知的。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是否作为HIV潜伏期的一部分。以及用于变性人激素替代疗法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影响一组潜伏期逆转剂（LRA）的活性，包括用于HIV根除临床试验的LRA。在目标2中，我们打算评估目前临床上使用的Toll样受体（TLR）激动剂的活性是否与Toll样受体（TLR）激动剂的活性相关。根除艾滋病毒的试验可能受到性激素和抗雄激素的影响。最后，在目标3中，探讨性激素和抗雄激素是否影响NK细胞活性。NK细胞是先天免疫系统的一部分，并在控制艾滋病毒感染方面发挥重要作用。性激素已经被证明对NK细胞抗肿瘤活性有不良影响。然而，关于性激素是否会影响抗艾滋病毒活性。在设计目标策略时，我们的研究将特别有趣努力消除包括妇女和变性人在内的不同艾滋病毒携带者中的艾滋病毒潜伏库，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。