Reducing the HIV Reservoir: Next-Generation Latency Reversal Agents and T Cell Population Targets

减少 HIV 病毒库：下一代潜伏期逆转剂和 T 细胞群目标

• 批准号: 10379457
• 负责人: Shane David Falcinelli
• 金额: $ 5.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379457
• 关键词: Adherence; Antigens; Biological Assay; CD4 Positive T Lymphocytes; Cell Compartmentation; Cell Proliferation; Cell Separation; Cells; Clinical; Clinical Research; DNA; Data; Detection; Development; Disease; Doctor of Philosophy; Drug Interactions; Drug resistance; Emodin; Environment; Exposure to; Financial Hardship; Frequencies; Future; Gene Expression; Generations; Genetic Transcription; Genome; HIV; HIV Core Protein p24; HIV Infections; HIV Seropositivity; HIV-1; Health; Healthcare Systems; Immune; Immune system; Incidence; Intervention; Laboratories; Length; Long-Term Effects; Lymphocyte; Measurement; Mentorship; Morbidity - disease rate; Nature; Outcome; Participant; Persons; Phylogenetic Analysis; Physicians; Population; Production; Proliferating; Proviruses; Public Health; RNA; Research; Research Project Grants; Resistance; Rest; Scientist; T-Lymphocyte; Target Populations; Techniques; Testing; Training; Universities; Viral; Viral Antigens; Viral Genome; Viral Proteins; Viral reservoir; Viremia; Virus; Virus Activation; Virus Diseases; antigen detection; antiretroviral therapy; chronic infection; clinically relevant; cost; detection assay; genome sequencing; immune clearance; immune function; interest; mortality; next generation; novel; prevent; protein expression; small molecule; social stigma; treatment effect; viral rebound

PROJECT SUMMARY/ABSTRACT The human immunodeficiency virus (HIV) is responsible for major morbidity, mortality, and cost to healthcare systems worldwide. While antiretroviral therapy (ART) provides a potent reduction of viremia and improvement in immune function, lifelong adherence is required to prevent viral rebound from the viral reservoir—latent, but replication competent proviral HIV DNA in the genomes of host CD4 T cell lymphocytes. Significantly, a lifetime of treatment is associated with financial burden, drug interactions, drug resistance, and unknown long-term effects of treatment. Furthermore, the stigma associated with HIV disease contributes to negative health outcomes. Thus, a cure for HIV is of substantial public health interest. A main strategy for HIV cure is the use of small-molecule latency reversal agents (LRAs) to induce viral expression in the latent reservoir so that the immune system can recognize and clear the reservoir. This viral reservoir is best understood within resting CD4 T lymphocytes. However, the nature of HIV persistence in other CD4 T cell populations (“non-resting”) is unknown. Understanding HIV persistence in non-resting CD4 T cells is important to determine whether exogenous interventions are necessary to deplete these cells in cure strategies. Thus, in AIM 1, we will characterize persistent HIV in resting versus non-resting CD4 T cells from ART-suppressed HIV seropositive participants using cell sorting, an array of viral reservoir measurement techniques, ultrasensitive antigen detection assays, and near-full length viral genome sequencing. In an effort to deplete the viral reservoir, several LRAs have been tested in clinical studies. However, LRAs used clinically to date only provide a small induction of viral expression, and none have depleted the reservoir. More potent next-generation LRAs are in development, however, the ability of these novel LRAs to induce sufficient viral protein expression in CD4 T cells for immune recognition and clearance is not well- defined. In addition, it is unknown whether non-resting CD4 T cells, despite being more transcriptionally active than resting CD4 T cells, can undergo spontaneous immune clearance without an LRA or if these cells represent another compartment of HIV persistence. Thus, in AIM 2 we will assess the ability of novel and potent next-generation LRAs to induce HIV expression sufficient for immune clearance in resting versus non-resting CD4 T cells using the techniques described above and a novel latency clearance assay. In addition to informing future efforts in HIV cure research, the project proposed herein fits perfectly into an intensive training plan for a productive clinician scientist at a top-tier research university. The pioneering environment of the UNC HIV Cure Center and the sponsors, David Margolis, MD and Nancie Archin, PhD will provide the mentorship necessary for the development of an outstanding clinician scientist in the HIV field.

项目总结/摘要 人类免疫缺陷病毒（HIV）是造成主要发病率、死亡率和治疗费用的原因。 全世界的医疗系统。虽然抗逆转录病毒疗法（ART）提供了有效的减少病毒血症， 免疫功能的改善，需要终身坚持，以防止病毒反弹，从病毒 宿主CD 4 T细胞淋巴细胞基因组中潜伏但有复制能力的前病毒HIV DNA。 值得注意的是，终生治疗与经济负担、药物相互作用、耐药性和 未知的长期治疗效果。此外，与艾滋病毒疾病有关的耻辱感有助于 负面的健康结果。因此，治疗HIV具有重大的公共卫生利益。 HIV治疗的主要策略是使用小分子潜伏期逆转剂（LRA）诱导病毒性逆转。 在潜伏的水库表达，使免疫系统可以识别和清除水库。这种病毒 最好在静息CD 4 T淋巴细胞中了解储存库。然而，艾滋病毒在其他地区的持续存在的性质 CD 4 T细胞群（“非静息”）未知。了解HIV在非静息CD 4 T细胞中的持久性 重要的是要确定是否需要外源性干预来耗尽这些细胞以进行治疗 战略布局因此，在AIM 1中，我们将描述静息与非静息CD 4 T细胞中持续存在的HIV 从ART抑制的HIV血清阳性参与者使用细胞分选，一系列病毒库测量 技术、超灵敏抗原检测分析和近全长病毒基因组测序。 为了减少病毒库，已经在临床研究中测试了几种LRA。然而，在这方面， 迄今为止，临床上使用的LRA仅提供了病毒表达的小诱导，并且没有一种能够耗尽病毒表达。 水库更有效的下一代LRA正在开发中，然而，这些新型LRA的能力， 在CD 4 T细胞中诱导足够病毒蛋白表达以用于免疫识别和清除并不是很好- 定义了此外，目前尚不清楚非静息CD 4 T细胞，尽管在转录上更活跃， 比静止的CD 4 T细胞，可以在没有LRA的情况下进行自发免疫清除，或者如果这些细胞 代表了艾滋病病毒持久性的另一部分。因此，在AIM 2中，我们将评估新的和 有效的下一代LRA诱导HIV表达，足以在静息状态下进行免疫清除 使用上述技术和新的潜伏期清除测定法比较非静息CD 4 T细胞。 除了为艾滋病治疗研究的未来努力提供信息外，本文提出的项目完全符合 一个在顶级研究型大学为一名多产的临床科学家提供的强化培训计划。开拓 艾滋病治疗中心的环境和赞助商，大卫马戈利斯，医学博士和南西阿钦，博士将 提供必要的指导，在艾滋病毒领域的杰出临床科学家的发展。