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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.

为了结束美国和世界范围内的流行病，必须采取多种方法