The HIV Reservoir in Women: Implications for HIV cure interventions

摘要 HIV持续感染长寿的静止记忆CD4T细胞，对当前的抗病毒药物无效 逆转录病毒疗法(ART)和不受免疫监测的影响仍然是努力 实现艾滋病毒根除。病毒的潜伏状态在感染后几天内建立，并迅速腐烂。 半衰期为40-44个月，需要终生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。这样的工作需要对所有人口的水库性质有广泛的了解。 人民。然而，我们对女性蓄水池的了解非常有限，因为这一群体传统上处于- 在艾滋病毒治疗相关研究中具有代表性。与女性感染艾滋病毒有关的几个特征，如 因为感染早期低病毒血症和保存的CD4T细胞计数可能会影响HIV储存库。因素 女性特有的，包括先天免疫和适应性免疫、遗传学和周期激素的差异 变化可能会影响HIV的发病机制、免疫功能，从而最终影响HIV的性格 潜伏的蓄水池，并影响清除持续性感染的治疗方法。在这个项目中，我们寻求一个) 静息T细胞亚群中具有复制能力的潜伏HIV感染频率的特征 妇女外周和解剖组织中的细胞；b)决定艾滋病毒储存库的稳定性 静息T细胞亚群随时间的变化；c)调查性激素影响的潜在差异 对干扰艾滋病毒潜伏期的试剂的反应性；d)调查效应细胞清除重新激活的能力 在生理水平的性激素存在的情况下感染；以及e)检查I型的作用 干扰素、干扰素-α在调节女性隐匿性蓄水池建立中的作用从这个过程中学到的知识 该项目将推动该领域在所有人口中开发成功的根除艾滋病毒的疗法 一群人。

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.