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。

基本信息

批准号：
8703593
负责人：
STEVEN Grant DEEKS
金额：
$ 730.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8703593
关键词：
Acquired Immunodeficiency Syndrome Address Adherence Anatomy Antiviral Response Apoptosis CD4 Positive T Lymphocytes Caring Cell Communication Cells Collaborations DNA Enzymes Epidemic Functional disorder Genetic Transcription Genome HIV HIV Infections Health Highly Active Antiretroviral Therapy Human Immune response Immune system Impairment Individual Infection Inflammatory Inflammatory Response Integration Host Factors Intervention Latent Virus Life Location Macaca mulatta Maintenance Mediating Myelogenous Myeloid Cells Natural regeneration Nature Pathologic Patients Persons Pharmaceutical Preparations Population Process Regimen Research Research Personnel Risk Role SIV Signal Transduction T-Cell Activation T-Lymphocyte Testing Therapeutic Agents Tissues Toxic effect Tryptophan 2,3 Dioxygenase Viral Viral Genome Virus Virus Latency Work antiretroviral therapy base collaboratory cytokine in vivo macrophage monocyte colony stimulating factor nonhuman primate prevent programs replication therapy research study virus host interaction

项目摘要

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.

描述（由申请人提供）：虽然目前的抗逆转录病毒疗法可以延长艾滋病毒感染者的生命，但它并不能完全恢复健康。这些药物通常具有显着的毒性。许多人无法维持维持益处所必需的长期坚持。这些药物价格昂贵，全球大多数有需要的人都无法获得。为了扭转疫情的蔓延并为所有人提供护理，需要采取根本不同的方法。其中一种方法是找到一种通过安全且可扩展的干预措施来治愈艾滋病毒感染者的方法。尽管标准疗法完全或接近完全抑制病毒复制，但具有复制能力的艾滋病毒在所有个体中无限期地持续存在。至少有三种机制有助于这种持久性：(1) 在长寿命 CD4+ T 细胞和骨髓细胞中维持转录沉默的原病毒基因组，(2) 潜伏感染细胞的增殖，并缓慢再生稳定的病毒库。 -分裂受感染的细胞，和/或（3）基于组织的病毒复制和细胞间传播的病灶，其可能部分由局部炎症反应驱动。我们的提案具有三个广泛定义的目标，旨在了解艾滋病毒持续存在的本质和逆转潜伏期。首先，我们将定义长期治疗期间具有复制能力的病毒的解剖学和细胞分布。其次，我们将研究有助于建立和维持 HIV 潜伏期的宿主机制，重点关注细胞间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中）有针对性的干预措施，旨在逆转潜伏期，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，他们在相互之间以及与他人之间有着长期的成功合作记录，并且相信治愈方法最终将部分取决于改变与艾滋病毒相关的宿主反应，而这些反应直接有助于病毒潜伏期。