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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.

项目总结/文摘