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: 9977116
• 负责人: Nancie M Archin
• 金额: $ 54.97万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977116
• 关键词: Address; Affect; Anatomy; 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; Estrogen receptor positive; 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; chronic infection; immune clearance; immune function; latent HIV reservoir; male; memory CD4 T lymphocyte; men; novel; preservation; 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 长寿命静息记忆 CD4+ T 细胞持续感染 HIV，对当前抗病毒药物无反应 逆转录病毒疗法（ART）且不受免疫监视的影响仍然是努力的巨大障碍 病毒的潜伏状态在感染后几天内就建立起来，并且很快就会消失。 缓慢，半衰期为 40-44 个月，需要终生抗病毒治疗以抑制复发 破坏持续性艾滋病毒感染的方式已成为治愈艾滋病毒的首要任务。 这项工作需要对所有人群中病毒宿主的性质有广泛的了解。 然而，我们对女性病毒宿主的了解非常有限，因为这个群体传统上缺乏了解。 与艾滋病毒治疗相关的研究中出现了一些与女性艾滋病毒感染相关的特征，例如 早期感染期间的低病毒血症和保留的 CD4 T 细胞计数可能会影响 HIV 储存库。 针对女性，包括先天性和适应性免疫、遗传学和周期性激素的差异 变化可能会影响HIV的发病机制、免疫功能，从而最终影响HIV的特征 潜伏病毒库，并影响清除持续性感染的治疗方法。在这个项目中，我们寻求 a) 表征静息 CD4 T 亚群中具有复制能力的潜伏 HIV 的感染频率 女性外周组织和解剖组织中的细胞；b) 确定女性体内 HIV 储存库的稳定性。 c) 研究随时间变化的静息 T 细胞亚群； d) 研究效应细胞清除重新激活的能力； 性激素生理水平存在下的感染；和 e) 检查 I 型的作用 干扰素、干扰素-α 调节女性潜在储存库的建立 从中获得的知识。 该项目将推动该领域开发成功的治疗方法，以在所有人群中根除艾滋病毒 的人。