Mechanisms of CTL Resistance in HIV Reservoirs

HIV病毒库中CTL耐药机制

基本信息

批准号：
10548335
负责人：
R. Brad Jones
金额：
$ 81.2万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548335
关键词：
Adherence Advanced Development Agonist Anti-Retroviral Agents Applications Grants Autologous BCL2 gene Biological Assay Biology CD4 Positive T Lymphocytes Candidate Disease Gene Cell Culture Techniques Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Clinical Trials Clone Cells Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Consultations Cytotoxic T-Lymphocytes Data Disease remission Dissection EZH2 gene Future Gene Expression Profiling Genes Genetic Transcription Goals Granzyme HIV HIV Infections Health Human Immune system Immunotherapy Impairment Individual Infection Intrinsic factor Lead Letters Leukapheresis Literature Malignant Neoplasms Mediating Microscopy Modernization Outcome Pathway interactions Persons Pharmaceutical Preparations Phenotype Play Predisposition Reporting Resistance Resolution Resource-limited setting Resources Role Sampling Sampling Studies Serine Proteinase Inhibitors Suggestion Technology Testing Therapeutic Time Treatment Efficacy Validation Viral reservoir Virus Work antagonist antiretroviral therapy arm base cell killing cell type differential expression effector T cell immune clearance improved in vitro Model in vivo insight next generation sequencing novel novel therapeutics overexpression resistance factors resistance gene resistance mechanism small molecule targeted treatment therapeutic candidate therapeutic target therapy development

项目摘要

PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. It would therefore be of tremendous value to develop novel therapies that can either cure HIV infection or drive it into remission (a state where levels of virus remain low or undetectable even when one stops taking ARV medication). One approach to achieving either a cure or remission is to reactivate latent (hidden) ‘reservoirs’ of virus and harness the immune system to reduce or eliminate these reservoirs. These ‘kick & kill’ approaches often focus on cytotoxic T-cells (CTL), which are an arm of the immune system specialized in eliminating virus-infected cells. While the ‘kick & kill’ strategy has shown promise in in vitro models of latency, it has not yet been effective in clinical trials. In recent work, we have uncovered an additional barrier to eliminating viral reservoirs by showing that HIV-infected cells are intrinsically resistant to CTL - even when they are forced to show virus to the immune system by latency reversing agents (LRAs). Although this idea of intrinsic resistance to CTL has not been widely considered in the context of HIV, it is well known as a factor that limits therapeutic efficacy in cancer. In this grant application we propose to leverage cutting edge technologies to identify novel mechanisms by which target cells resist elimination by CTL. These approaches are expected to yield a large number of ‘hits’, for which we will perform high-resolution mechanistic characterizations. We will then study samples from people living with HIV to determine which of these mechanisms of resistance play roles in HIV persistence in vivo. Finally, we will directly test whether therapies targeting this resistance can allow CTL to kill these ex vivo reservoir-harboring cells. We expect that the outcome of our study will be the identification of novel targets for the development of therapies aimed at curing HIV infection or enabling remission. More broadly, we anticipate that the mechanisms identified here will provide fundamental insights into the biology of CTL with implications for cancer & other conditions.

项目概要/摘要尽管现代疗法极大地改善了艾滋病毒感染者的前景，但它们无法治愈感染，使这些人终生承受抗逆转录病毒（ARV）药物治疗的负担。对于任何特定的个人来说，维持终生坚持用药可能会带来巨大的挑战。此外，许多人无法获得这些昂贵的药物，尤其是那些生活在因此，开发能够实现以下任一目的的新疗法将具有巨大的价值。治愈艾滋病毒感染或使其进入缓解状态（即使在病毒感染的情况下，病毒水平仍然较低或无法检测到的状态）一种实现治愈或缓解的方法是重新激活潜伏的抗逆转录病毒药物。（隐藏的）病毒“储存库”，并利用免疫系统来减少或消除这些储存库。 “杀灭”方法通常侧重于细胞毒性 T 细胞 (CTL)，它是免疫系统的一个分支，专门负责虽然“踢杀”策略在体外潜伏模型中显示出希望，但它在临床试验中尚未有效，在最近的工作中，我们发现了消除的另一个障碍。通过证明感染 HIV 的细胞对 CTL 具有内在抵抗力，即使在被迫的情况下，也能发现病毒库通过潜伏逆转剂（LRAs）向免疫系统显示病毒，尽管这种想法具有内在抵抗力。 CTL 尚未在 HIV 背景下得到广泛考虑，但众所周知，它是限制治疗的一个因素在这项拨款申请中，我们建议利用尖端技术来识别新的癌症疗效。靶细胞抵抗 CTL 消除的机制预计将产生巨大的效果。 “命中”的数量，我们将对其进行高分辨率机械表征。来自艾滋病毒感染者的样本，以确定哪些耐药机制在艾滋病毒中发挥作用最后，我们将直接测试针对这种耐药性的疗法是否可以使 CTL 杀死。我们期望我们的研究结果将是新的体内储存细胞的鉴定。更广泛地说，我们的目标是开发旨在治愈艾滋病毒感染或实现缓解的疗法。预计这里确定的机制将为 CTL 生物学提供基本见解对癌症和其他疾病的影响。