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

• 批准号: 9291553
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291553
• 关键词: Anti-HIV Agents; Anti-Retroviral Agents; 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; Stem cells; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Viral; Virus; Virus Replication; Withdrawal; Work; attenuation; base; cancer therapy; chemical property; chromatin immunoprecipitation; combinatorial; design; high throughput screening; histone demethylase; in vivo; innovation; integration site; killings; member; novel; novel strategies; novel therapeutics; planetary Atmosphere; prevent; promoter; purge; small molecule; success; transcription factor

 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）无法根除感染者体内的病毒。因此，迫切需要新的治疗策略来攻击潜伏感染病毒库并防止ART撤出后病毒反弹。在过去的十年中，在几种体外细胞模型或离体模型中，在鉴定几种可以重新激活潜伏 HIV 而不激活 CD4+ T 细胞的小分子方面取得了巨大进展。然而，这些化合物不能逆转体内HIV潜伏期。这对根除 HIV 构成了巨大障碍，并表明基于细胞模型的研究必须使用来自接受抑制治疗的无病毒血症患者的原代 T 细胞进行验证。通过对能够重新激活沉默病毒位点的小化合物进行高通量筛选，我们最近鉴定了一组新颖且独特的 70 种具有潜伏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）。该研究项目旨在利用基于细胞的模型和离体方法，利用从德克萨斯大学艾滋病毒诊所获得的无病毒血症患者的原代 T 细胞，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。西南医学中心校园。这项研究不仅将使我们对潜伏期的分子基础有更好的基本了解，还将阐明新型潜伏期重新激活剂和用于根除患者艾滋病毒的创造性组合策略。拟议的工作建立在最近发表的一篇文章和一组新颖的初步数据的基础上，这些数据将 SMORE 确定为清除潜在 HIV 病毒库的新候选者。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 UT 进行。西南医学中心，在药理学和免疫学等互补领域拥有最先进的技术和非常丰富的合作氛围。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，以在我们向功能性治愈的竞赛中瞄准艾滋病毒潜伏期。