DARE: Delaney AIDS Research Enterprise to find a cure.

敢于：德莱尼艾滋病研究企业寻找治疗方法。

• 批准号: 8185246
• 负责人: STEVEN Grant DEEKS
• 金额: $ 430.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185246
• 关键词: DARE; Delaney; AIDS; Research; Enterprise

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. PUBLIC HEALTH RELEVANCE: The major barrier to curing HIV infection is a reservoir of long-lived cells that contain replication-competent virus. We believe that a comprehensive assessment of the reservoir together with the in vivo testing of possible interventions aimed at reversing this process will almost certainly advance the field, and could in five years provide the rationale for advanced testing in humans of single or combination regimens aimed at fully eradicating HIV from an infected person. Project 1: Myeloid- T Cell Interactions That Sustain SIV Reservoirs During Effective Antiretroviral Therapy Project Leader (PL): Dr. Joseph McCune (Description as provided by applicant) HIV persistence in the optimally-treated patient is sustained by the maintenance of transcriptionally-silent proviral genomes within cell populations that are long-lived or that turn over slowly, and/or by ongoing low-level viral replication leading to de novo infection of target cells. It is a central theme of this Collaboratory that such persistence/latency of HIV is maintained by tissue-based interactions between CD4[+] T cells and myeloid cells through one or more mechanisms, including: (1) efficient cell-to-cell transfer of HIV; (2) regulatory signals that result in CD4[+] T cell dysfunction and impairment of the antiviral response; (3) myeloid signaling to CD4[+] T cells that results in maintenance of transcriptional silencing; and (4) inflammatory signals which result in CD4[+] T cell activation and increased risk of either de novo infection or reactivation of latently infected cells and replenishment of long-lived infected cells. Additionally, HIV infection may induce factors that promote survival of infected cells and, hence, of a long-lived viral reservoir. To determine which of these mechanisms are operative, we will first systemically interrogate the tissue spaces of the optimally treated host, so that the location and size of the latent and actively replicating reservoir can be determined. Given the availability of therapeutic agents that impact upon these mechanisms, we will then test definitively to what extent they might contribute to virus persistence/latency, alone or in concert. In this Project, this approach is taken in the context of SIV infection of the rhesus macaque (Macaca mulatta), pursuing experiments in the following Specific Aims: (1) to determine whether and how foci of persistently replicating and/or latent virus are sustained in the optimally-treated host by pathologic myeloid-T cell interactions; (2) to determine whether the persistent/latent virus pool can be diminished by inhibition of indoleamine 2,3-dioxygenase (IDO), an immunoregulatory enzyme that mediates the pro-inflammatory effects of myeloid cells on CD4+ T cells; and (3) to determine whether the persistent/latent virus pool can be diminished by inhibition of monocyte colony stimulating factor (MCSF), a cytokine which is upregulated by SIV/HIV and that prevents apoptosis of macrophages. RELEVANCE: Interacting closely with the work in Projects 2-5 and 7, this Project will explore the extent to which various interactions between CD4"' T cells and myeloid cells are associated with persistence/latency of SIV virus after the initiation of ART. We will also develop a quantitative framework by which to assess changes in the total body load of viral genomes, before and after each mechanism is interrupted pharmacologically in vivo.

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CD4+T细胞和髓样细胞中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。 与公共卫生相关：治愈艾滋病毒感染的主要障碍是含有复制能力病毒的长寿命细胞的储存库。我们认为，对宿主进行全面评估，以及对旨在扭转这一进程的可能干预措施进行体内测试，几乎肯定会推动这一领域的发展，并可在五年内为在人体内进行旨在彻底根除感染者艾滋病毒的单一或联合方案的先进测试提供理论依据。 项目1：在有效的抗逆转录病毒治疗期间维持SIV储存库的髓系-T细胞相互作用 项目负责人(PL)：约瑟夫·麦库恩博士 (申请人提供的描述)在接受最佳治疗的患者中，艾滋病毒的持久性是通过维持细胞群体中转录沉默的前病毒基因组来维持的，这些基因组活得很长或翻转得很慢，和/或通过持续的低水平病毒复制导致目标细胞的从头感染。这个合作实验室的一个中心主题是，通过一种或多种机制，通过一种或多种机制，在CD4[+]T细胞和髓系细胞之间基于组织的相互作用来维持HIV的这种持久性/潜伏期，包括：(1)有效的细胞间转移；(2)导致CD4[+]T细胞功能障碍和抗病毒反应受损的调节信号；(3)髓系信号向CD4[+]T细胞传递导致转录沉默的维持；(4)炎症信号导致CD4[+]T细胞活化，增加从头感染或潜伏感染细胞重新激活和长期感染细胞补充的风险。此外，艾滋病毒感染可能诱导促进受感染细胞存活的因素，从而促进长寿的病毒库的存活。为了确定这些机制中的哪一种是有效的，我们将首先系统地询问经过优化处理的宿主的组织空间，以便可以确定潜在的和活跃的复制储存库的位置和大小。考虑到影响这些机制的治疗剂的可用性，我们将最终测试它们对病毒持久性/潜伏期的贡献程度，无论是单独还是协同作用。在本项目中，这一方法是在SIV感染恒河猴(Macaca Mulatta)的背景下进行的，旨在进行以下特定目标的实验：(1)确定持续复制和/或潜伏病毒的病灶是否以及如何通过病理性的髓系T细胞相互作用维持在最佳治疗的宿主中；(2)确定是否可以通过抑制吲哚胺2，3-双加氧酶(IDO)来减少持久/潜伏病毒池，吲哚胺2，3-双加氧酶(IDO)是一种免疫调节酶，介导髓系细胞对CD4+T细胞的促炎效应；以及(3)确定是否可以通过抑制单核细胞集落刺激因子(MCSF)来减少持久/潜伏的病毒库，单核细胞集落刺激因子是SIV/HIV上调的一种细胞因子，可以防止巨噬细胞的凋亡。 相关性：与项目2-5和7中的工作密切相关，该项目将探索在ART启动后，T细胞和髓系细胞之间的各种相互作用与SIV病毒的持久性/潜伏期相关的程度。我们还将开发一个定量框架，用于评估病毒基因组在体内药理学中断前后的总体内负荷的变化。