A New Approach to Reactivating HIV from Latency

重新激活潜伏期艾滋病毒的新方法

基本信息

批准号：
10212924
负责人：
ASHLEY T. HAASE
金额：
$ 59.96万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212924
关键词：
Active Sites Anatomy Attenuated Biological Assay CD4 Positive T Lymphocytes Cell Culture Techniques Cells Cellular Assay Coupled Data Development Evaluation Failure Feedback Gene Expression Gene Silencing Genetic Transcription Genome Goals Growth HIV HIV Genome HIV Infections Histone Deacetylase Inhibitor In Vitro Infection Interphase Cell Interruption Intervention Investigation Lead Lentivirus Vector Lymphoid Tissue Measurement Measures Medical History Methods Mitogens Patients Proviruses RNA Viruses Sampling Shock Supplementation T-Cell Activation T-Cell Receptor T-Lymphocyte Transactivation Viral Virus antiretroviral therapy base cofactor epigenetic silencing genome analysis immune clearance improved in vitro Assay in vivo latent infection novel strategies peripheral blood reactivation from latency small molecule tat Genes vector-induced

项目摘要

SUMMARY/ABSTRACT Combination antiretroviral therapy (ART) can control but not cure HIV infection because of reservoirs, particularly latently infected CD4 T cells, established before ART was begun, from which infection rebounds if ART is interrupted. To achieve a functional cure or eradication of this reservoir, “shock and kill” strategies seek to reactivate latently infected CD4+ T-cells for elimination by immune or other mechanisms, but current methods for reactivation predicated on the concept that harbor HIV proviruses that have been transcriptionally silenced by epigenetic or other mechanisms have proven quite inefficient in reversing latency. This proposal describes a new approach to reactivating latently infected cells by lentivirus vector induced expression of the HIV tat gene. Preliminary results provide evidence of extraordinary efficiency of Tat-reactivation and the underpinnings for an in vitro latency reactivation assay with new single cell measurements of the latently infected cell reservoir from which infection will rebound if ART is interrupted. The Specific Aims of the proposal are to 1) further develop the Tat-reactivation assay as a faster and more accurate assay for reservoir evaluations in peripheral blood (PB) and lymphoid tissues (LT); determine the correlations between single cell measurements of virus producing cells, cells with intact HIV genomes and current quantitative virus growth assays; and 2) apply the assay to assess the impact of ART in very early stage infection to limit the size of HIV reservoirs in PB and LT. peripheral blood (PB) and lymphoid tissues (LT). The long-term goal of investigation of Tat-reactivation is development of more effective approaches to the “shock” component of shock and kill approaches to reducing HIV reservoirs.

摘要/摘要联合抗逆转录病毒疗法（ART）可以控制但不能治愈艾滋病毒感染，因为艾滋病毒储存库，特别是潜伏感染的 CD4 T 细胞，在 ART 开始之前建立，如果出现以下情况，感染就会反弹：为了实现治疗功能或根除该病毒库，需要采取“休克和杀灭”策略。重新激活潜伏感染的 CD4+ T 细胞，通过免疫或其他机制消除，但目前重新激活方法基于包含已转录的 HIV 原病毒的概念事实证明，表观遗传或其他机制的沉默在逆转潜伏期方面效率相当低。描述了一种通过慢病毒载体诱导的表达来重新激活潜伏感染细胞的新方法 HIV tat 基因的初步结果提供了 Tat 重新激活的非凡效率的证据。体外潜伏期再激活测定的基础是新的单细胞潜伏期测量如果 ART 中断，感染将会反弹的受感染细胞库该提案的具体目标。 1) 进一步开发 Tat 重新激活检测，作为一种更快、更准确的储库检测方法外周血（PB）和淋巴组织（LT）的评估确定单细胞之间的相关性；测量病毒产生细胞、具有完整 HIV 基因组的细胞和当前定量病毒生长检测；2) 应用该检测来评估 ART 在极早期感染中限制 HIV 大小的影响 PB 和 LT 中的储库研究的长期目标。 Tat 重新激活的目的是开发更有效的方法来应对休克和杀戮的“休克”部分减少艾滋病毒储存库的方法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Initial productive and latent HIV infections originate in vivo by infection of resting T cells.

DOI：
10.1172/jci171501
发表时间：
2023-11-15
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Wietgrefe, Stephen W.;Anderson, Jodi;Duan, Lijie;Southern, Peter J.;Zuck, Paul;Wu, Guoxin;Howell, Bonnie J.;Reilly, Cavan;Kroon, Eugene;Chottanapund, Suthat;Buranapraditkun, Supranee;Sacdalan, Carlo;Tulmethakaan, Nicha;Colby, Donn J.;Chomchey, Nitiya;Prueksakaew, Peeriya;Pinyakorn, Suteeraporn;Trichavaroj, Rapee;Mitchell, Julie L.;Trautmann, Lydie;Hsu, Denise;Vasan, Sandhya;Manasnayakorn, Sopark;de Souza, Mark;Tovanabutra, Sodsai;Schuetz, Alexandra;Robb, Merlin L.;Phanuphak, Nittaya;Ananworanich, Jintanat;Schacker, Timothy W.;Haase, Ashley T.
通讯作者：
Haase, Ashley T.