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：艾滋病毒潜伏期是一个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）不会放射受感染者的病毒。因此，迫切需要迫切需要攻击潜在感染的储层并防止病毒反弹的新型治疗策略。在过去的十年中，在识别几个可以在几个基于体外细胞或离体模型中激活CD4+ T细胞的小分子中取得了巨大进展。但是，这些化合物不会在体内逆转艾滋病毒潜伏期。这为根除HIV构成了一个巨大的障碍，并表明必须使用抑制性治疗的恶毒患者的原代T细胞来验证基于细胞模型的研究。使用高通量筛选，对能够重新激活沉默的病毒基因座的小型化合物，我们最近确定了一种新型且独特的70种铅化合物，具有潜伏期反应的潜力，我们将其命名为Smore smore smore smore for小分子重新激活器。该研究项目的目的是进一步表征这些小型化合物的效力，效率，细胞毒性和基本作用机理，并使用基于细胞的模型和离体方法与来自U.T. HIV诊所获得的Avirematimem患者的原代T细胞进行了体内T细胞。西南医疗中心校园。这项研究不仅会使我们对潜伏期的分子基础有更好的基本了解，而且还将阐明新型的潜伏期反应剂和创造性的综合策略，以消除患者的HIV。拟议的作品建立在最近的出版物和一套新颖的初步数据的基础上，这些数据将Smore确定为清除潜在艾滋病毒储量的新型候选人。鉴于SMERE重新激活提供商的转录，它们成为HIV感染患者的合理HIV消除策略的关键候选者。该项目将在U.T.西南医学中心，拥有最先进的技术，并且在药理学和免疫学等完整领域的合作者中非常丰富的氛围。总的来说，这些发现将扩大我们的治疗方法和组合策略的范围，以将艾滋病毒潜伏期瞄准我们的种族降低到功能治疗。