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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.

产品说明：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宿主并防止ART停药后病毒反弹。在过去的十年中，在鉴定几种小分子方面取得了很大进展，这些小分子可以在几种基于体外细胞或离体模型中重新激活潜伏的HIV而不激活CD4+ T细胞。然而，这些化合物不能逆转体内HIV潜伏期。这对根除HIV构成了很大的障碍，并表明基于细胞的模型研究必须使用来自接受抑制治疗的病毒血症患者的原代T细胞进行验证。使用高通量筛选能够重新激活沉默的病毒位点的小化合物，我们最近确定了一组新的和独特的70个先导化合物，具有潜在的重新激活潜力，我们命名为SMORE的小分子再激活剂。该研究项目旨在进一步表征这些小化合物的效力，功效，细胞毒性和基本作用机制，使用基于细胞的模型和离体方法，使用来自德克萨斯大学HIV诊所的病毒血症患者的原代T细胞。西南医学中心校园这项研究不仅将使我们更好地了解潜伏期的分子基础，而且还将阐明新型潜伏期激活剂和创造性的组合策略，用于根除患者中的HIV。这项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SMORE确定为清除潜伏的HIV储存库的新候选者。鉴于SMORE重新激活前病毒转录，它们成为HIV感染患者中合理的HIV根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，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，以靶向HIV潜伏期，从而实现功能性治疗。