A New Approach to Reactivating HIV from Latency

重新激活潜伏期艾滋病毒的新方法

• 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
• 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

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.

总结/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， 特别是在ART开始前建立的潜伏感染的CD 4 T细胞，如果 艺术中断了。为了实现对这一储存库的功能性治愈或根除，“休克和杀死”战略寻求 重新激活潜伏感染的CD 4 + T细胞，通过免疫或其他机制消除，但目前 基于携带HIV前病毒的概念的再激活方法， 通过表观遗传或其他机制沉默的基因在逆转潜伏期方面被证明是非常低效的。这项建议 描述了一种通过慢病毒载体诱导表达 HIV达特基因。初步结果提供了证据，证明了Tat-再活化的非凡效率， 用新的单细胞测量潜伏性细胞因子的体外潜伏性再激活试验的基础 如果ART中断，感染将从感染细胞库反弹。提案的具体目标 1）进一步开发Tat-再活化测定法，作为用于储库的更快和更准确的测定法， 外周血（PB）和淋巴组织（LT）中的评价;确定单细胞之间的相关性 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的测量 检测; 2）应用该检测来评估ART在非常早期感染中的影响，以限制HIV的大小 外周血（PB）和淋巴组织（LT）中的储存库。调查的长期目标 重新激活Tat的方法是发展更有效的方法来处理休克和杀死的“休克”部分 减少艾滋病毒储存库的方法。

项目成果

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.