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Novel small molecules to reactivate latent HIV and sensitize to anti-viral therapies

新型小分子可重新激活潜伏的艾滋病毒并使抗病毒疗法敏感

基本信息

批准号：
9535050
负责人：
Ivan D'Orso
金额：
$ 48.49万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9535050
关键词：
Anti-HIV Agents Antiviral Agents Antiviral Therapy Blood specimen CD4 Positive T Lymphocytes Cell Death Cell Line Cells Cessation of life Chemicals Chromatin Clinic Complex DNA Damage DNA Repair Data Enzymes Epigenetic Process Etoposide Genes Genetic Transcription Genomics Goals HIV HIV Genome HIV Seropositivity Health Histone Deacetylase Inhibitor Human Immunology In Vitro Individual Knowledge Lead Life Cycle Stages Mammalian Cell Measures Medical center Memory Modeling Molecular Names Patients Pharmaceutical Preparations Pharmacology Property Proviruses Publications Race Radiosensitization Research Project Grants Specificity T-Lymphocyte Technology Testing Therapeutic Therapeutic Agents Toxic effect Viral Virus Virus Replication Withdrawal Work antiretroviral therapy attenuation base cancer therapy chemical property chromatin immunoprecipitation combinatorial design high throughput screening histone demethylase in vivo innovation integration site member novel novel strategies novel therapeutics planetary Atmosphere prevent promoter public health relevance purge reactivation from latency small molecule stem-like cell success transcription factor viral rebound virtual

项目摘要

DESCRIPTION: HIV latency is a widely accepted health problem because the drugs that curb viral replication (anti-retroviral therapy, ART) do not eradicate the virus from the infected individual. Therefore, novel therapeutic strategies to attack the latently infected reservoirs and prevent a rebound of virus after withdrawal of ART are urgently needed. Over the past decade, great progress has been made in identifying several small molecules that can reactivate latent HIV without activating CD4+ T cells in several in vitro cell-based or in ex vivo models. However, these compounds do not reverse HIV latency in vivo. This poses a great barrier for the eradication of HIV and suggests that studies in cell-based models must be validated using primary T cells from aviremic patients under suppressive therapy. Using a high-throughput screening for small compounds capable of reactivating silenced viral loci, we have recently identified a novel and unique set of 70 lead compounds with latency-reactivating potential that we named SMORE for Small MOlecule REactivators. This research project aims at further characterizing these small compounds for their potency, efficacy, cell toxicity and basic mechanism of action using both cell-based models and ex vivo approaches with primary T cells from aviremic patients obtained from the HIV Clinics at the U.T. Southwestern Medical Center campus. This study will lead us not only to a better basic understanding of the molecular underpinnings of latency but will also elucidate novel latency-reactivating agents and creative combinatorial strategies for HIV eradication in patients. The work proposed builds on a recent publication and a novel set of preliminary data that identified SMORE as novel candidates to purge latent HIV reservoirs. Given that SMORE reactivate proviral transcription, they emerge as key candidates for rational HIV eradication strategies in HIV infected patients. The project will be conducted at U.T. Southwestern Medical Center, which has state-of-the-art technologies and a very rich atmosphere of collaborators in complementary fields such as pharmacology and immunology. Collectively, these discoveries will expand our spectrum of therapeutic approaches and combinatorial strategies to target HIV latency in our race towards a functional cure.

描述：HIV潜伏期是一个被广泛接受的健康问题，因为抑制病毒复制的药物(抗逆转录病毒疗法，ART)不能从感染者身上根除病毒。因此，迫切需要新的治疗策略来攻击潜伏感染的水库，并防止ART停用后病毒反弹。在过去的十年里，在几个基于细胞的体外模型或体外模型中，在识别能够在不激活CD4+T细胞的情况下重新激活潜伏的HIV的小分子方面取得了很大的进展。然而，这些化合物并不能逆转HIV在体内的潜伏期。这对根除HIV构成了一个巨大的障碍，并表明在细胞模型中的研究必须使用来自接受抑制治疗的无血症患者的原始T细胞来验证。通过对能够重新激活沉默的病毒基因座的小分子化合物的高通量筛选，我们最近发现了一组新颖而独特的70种具有潜伏期重新激活潜力的先导化合物，我们将其命名为Smore小分子重新激活剂。这项研究项目旨在通过基于细胞的模型和体外方法，进一步表征这些小化合物的效力、疗效、细胞毒性和基本作用机制。这些T细胞来自德克萨斯州西南医学中心校区HIV诊所的无核症患者。这项研究不仅将使我们更好地了解潜伏期的分子基础，而且还将阐明新的潜伏期复活剂和创造性的组合策略来根除患者的艾滋病毒。这项拟议的工作建立在最近的一份出版物和一组新的初步数据的基础上，这些数据将斯莫尔确定为清除潜在艾滋病毒宿主的新候选者。鉴于Smore重新激活前病毒转录，它们成为艾滋病毒感染患者合理根除艾滋病毒策略的关键候选对象。该项目将在德克萨斯大学西南医学中心进行，该中心拥有最先进的技术，在药理学和免疫学等互补领域拥有非常丰富的合作者氛围。总而言之，这些发现将扩大我们的治疗方法和组合策略的范围，以针对我们朝着功能性治愈的竞赛中的艾滋病毒潜伏期。