The HIV Reservoir in Women: Implications for HIV cure interventions

女性艾滋病毒储存库：对艾滋病毒治疗干预措施的影响

• 批准号: 9411326
• 负责人: Nancie M Archin
• 金额: $ 54.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411326
• 关键词: Address; Affect; Anatomy; Anti-Retroviral Agents; Antigens; Antiviral Therapy; Area; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cells; Characteristics; Complex; Cross-Sectional Studies; Disease; Disease remission; Effector Cell; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Female; Frequencies; Gender; Genetic; Genetic Transcription; Gonadal Steroid Hormones; HIV; HIV Infections; HIV-1; Half-Life; Hormonal; Hormonal Change; Immune; Immunologic Surveillance; In Vitro; Infection; Interferon Type I; Interferon-alpha; Intervention; Knowledge; Lead; Life; Maintenance; Mediating; Memory; Modality; Natural Immunity; Natural Killer Cells; Nature; Participant; Pathogenesis; Periodicity; Physiological; Planets; Population; RNA; Recrudescences; Research Priority; Rest; Role; Signal Transduction; T memory cell; T-Lymphocyte; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Viremia; Virus; Woman; adaptive immunity; antiretroviral therapy; beta catenin; immune clearance; immune function; male; memory CD4 T lymphocyte; men; novel; promoter; reactivation from latency; receptor expression; reproductive tract; small molecule; therapeutic development

Abstract Persistent HIV infection of long lived resting memory CD4+ T-cells, unresponsive to current anti- retroviral therapy (ART) and unaffected by immune surveillance remains a formidable barrier to efforts to achieve HIV eradication. The latent state of the virus is established within days of infection, and decays very slowly with a half-life of 40-44 months, necessitating life-long antiviral therapy to suppress recrudescence of infection. Modalities to disrupt persistent HIV infection have become a priority in the quest to cure HIV infection. Such an undertaking requires broad knowledge of the nature of the reservoir in all populations of people. However, our knowledge of the reservoir in women is greatly limited as this group is traditionally under- represented in HIV cure related studies. Several characteristics associated with HIV infection in women, such as low viremia during early infection and preserved CD4 T cell count could impact the HIV reservoir. Factors specific to women, including differences in innate and adaptive immunity, genetics and cyclical hormonal changes may affect HIV pathogenesis, immune function, and thereby ultimately affect the character of the latent reservoir, and influence therapeutic approaches to clear persistent infection. In this project, we seek to a) characterize the frequency of infection of replication competent latent HIV in subpopulations of resting CD4 T- cells in both the periphery and anatomical tissues in women; b) determine the stability of the HIV reservoir in subpopulations of resting T-cells over time; c) investigate potential sex hormone-influenced differences in responsiveness to agents that disrupt HIV latency; d) investigate the ability of effector cells to clear reactivated infection in the presence of physiological levels of sex hormones; and e) examine the role of the Type I interferon, IFN-α in modulating establishment of the latent reservoir in women. Knowledge gained from this project will advance the field towards developing successful therapeutics for HIV eradication in all populations of people.

抽象的 长期存在的静止记忆CD4+ T细胞的持续性HIV感染，对电流抗抗反应无反应 逆转录病毒疗法（ART）和不受免疫监视的影响仍然是努力的巨大障碍 消除艾滋病毒。该病毒的潜在状态在感染的几天内建立，并且腐烂非常 半衰期为40-44个月的半衰期，必要的终身抗病毒疗法抑制了 感染。破坏持续性艾滋病毒感染的方式已成为寻求艾滋病毒的优先事项 感染。这样做的需要广泛了解储层的本质 人们。但是，我们对女性水库的了解受到了极大的限制，因为这个群体传统上是不足的 在HIV治疗相关研究中代表。与女性艾滋病毒感染有关的几种特征 由于早期感染和保存的CD4 T细胞计数中的病毒血症低可能会影响HIV储量。因素 特定于妇女，包括先天和适应性免疫学，遗传学和周期性的horsemonal的差异 变化可能会影响HIV发病机理，免疫功能，从而最终影响 潜在水库和影响疗法清除持续感染的方法。在这个项目中，我们寻求A） 表征复制的感染频率在静止CD4 T-的亚群中胜任的潜在艾滋病毒 女性周围和解剖组织中的细胞； b）确定艾滋病毒水库在 随着时间的流逝，静止的T细胞的亚群； c）调查潜在的性马酮影响的差异 对破坏艾滋病毒潜伏期的药物的反应； d）研究效应细胞清除重新激活的能力 在身体水平的性恐怖片中感染； e）检查I型的作用 干扰素，IFN-α在调节妇女中的潜在储层建立。从中获得的知识 项目将使该领域朝着在所有人群中开发成功消除艾滋病毒的疗法 人。