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.

摘要 长期存活的静息记忆CD 4 + T细胞的持续HIV感染，对当前抗- 逆转录病毒疗法（ART）和免疫监视的影响仍然是一个巨大的障碍，努力 实现艾滋病毒根除。病毒的潜伏状态在感染后的几天内建立，并迅速衰减。 缓慢，半衰期为40-44个月，需要终身抗病毒治疗，以抑制复发 感染阻断艾滋病毒持续感染的方法已成为寻求治愈艾滋病毒的优先事项 感染这项工作需要所有人口对水库的性质有广泛的了解， 人然而，我们对妇女的知识储备是非常有限的，因为这个群体传统上是在- 艾滋病治疗相关研究中的代表。与妇女感染艾滋病毒有关的几个特征，如 因为早期感染期间的低病毒血症和保存的CD 4 T细胞计数可能影响HIV储库。因素 具体到妇女，包括先天和适应性免疫，遗传和周期性激素的差异 变化可能影响艾滋病病毒的发病机制、免疫功能，从而最终影响人的性格 潜在水库，并影响治疗方法，以清除持续感染。在这个项目中，我们寻求a） 表征静息CD 4 T细胞亚群中有复制能力的潜伏HIV的感染频率， B）确定HIV储库在女性外周和解剖组织中的稳定性， c）研究静息T细胞亚群随时间的变化; d）研究效应细胞清除再活化的HIV抗体的能力; 在生理水平的性激素存在下的感染;和e）检查I型 干扰素、IFN-α在调节女性潜伏性储库建立中的作用。从这件事中获得的知识 该项目将推动该领域朝着开发成功的治疗方法，在所有人群中根除艾滋病毒的方向发展 的人。