DARE: Delaney AIDS Research Enterprise to find a cure.

描述(申请人提供)：虽然目前的抗逆转录病毒疗法延长了艾滋病毒感染者的生命，但它不能完全恢复健康。这些药物往往有很大的毒性。许多人无法维持维持福利所需的长期坚持。这些药物价格昂贵，全球大多数需要它们的人都无法获得。为了扭转疫情的传播并为所有人提供护理，需要采取一种根本不同的方法。其中一种方法是确定一种通过安全和可扩展的干预措施治愈艾滋病毒感染者的方法。尽管用标准疗法完全或几乎完全抑制了病毒复制，但具有复制能力的艾滋病毒在所有人中无限期地存在。至少有三种机制有助于这种持久性：(1)在长寿命的CD4T细胞和髓样细胞内维持转录沉默的前病毒基因组，(2)潜伏感染细胞的增殖与稳定的缓慢分裂的感染细胞库的再生，和/或(3)部分由局部炎症反应驱动的病毒复制和细胞间传播的组织灶性病变。我们的提案有三个广泛定义的目标，旨在了解艾滋病毒持久性和扭转潜伏期的性质。首先，我们将定义在长期治疗期间存在的具有复制能力的病毒的解剖和细胞分布。其次，我们将研究有助于建立和维持HIV潜伏期的宿主机制，重点关注细胞之间的相互作用在沉默整合的HIV DNA转录和/或以其他方式维持其持久性方面所起的作用。第三，我们将开发和测试(在非人类灵长类动物和人类身上)有针对性的干预措施，旨在扭转潜伏期，而不广泛激活免疫系统和/或DNA转录。为了实现这些目标，我们召集了一组研究人员，他们彼此之间和其他人之间有着长期的成功合作记录，他们相信治愈最终将在一定程度上取决于修改直接导致病毒潜伏的艾滋病毒相关宿主反应。

DESCRIPTION (provided by applicant): Although current antiretroviral therapy prolongs the life of HIV-infected individuals, it does not fully restore health. These drugs often have significant toxicities. Many individuals are not able to maintain long-term adherence necessary to maintain benefit. The drugs are expensive and are not available to most of the people globally who need them. To reverse the spread of the epidemic and to provide care for all, a fundamentally different approach is needed. One such approach would be to identify a means to cure HIV-infected people with a safe and scalable intervention. Despite complete or near complete inhibition of viral replication with standard therapies, replication-competent HIV persists indefinitely in all individuals. There are at least three mechanisms that contribute to this persistence: (1) maintenance of transcriptionally-silent proviral genomes within long-lived CD4+ T cells and myeloid cells, (2) proliferation of latently-infected cells with regeneration of a stable reservoir of slowly-dividing infected cells, and/or (3) tissue-based foci of viral replication and cell-to-cell spread that may be driven in part by local inflammatory responses. Our proposal has three broadly defined objectives that are aimed at understanding the nature of HIV persistence and reversing latency. First, we will define the anatomic and cellular distribution of replication-competent virus resides during long-term therapy. Second, we will investigate the host mechanisms that contribute to the establishment and maintenance of HIV latency, focusing on the role that cell-to-cell interactions have in silencing the transcription of integrated HIV DNA and/or otherwise maintaining its persistence. Third, we will develop and test (in non-human primates and in humans) targeted interventions aimed at reversing latency without broadly activating the immune system and/or DNA transcription. To address these objectives, we have assembled a group of investigators who have a long track record of successful collaboration, with each other and with others, and who believe that a cure will ultimately depend in part on modifying HIV-associated host responses that directly contribute to viral latency.