Targeted delivery of cytopathicity enhancing agents, and co-ordination with shock and kill, to reduce HIV reservoirs

有针对性地递送细胞病变增强剂，并与休克和杀伤相配合，以减少艾滋病毒储存库

• 批准号: 10447148
• 负责人: Darrell J Irvine
• 金额: $ 77.41万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447148
• 关键词: Adherence; Anti-Retroviral Agents; Antigen Targeting; Apoptosis; BCL2 gene; BCL2L1 gene; Biological Assay; CD4 Positive T Lymphocytes; Cause of Death; Cell model; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Cytosol; Cytotoxic T-Lymphocytes; Development; Disease remission; Drug Targeting; Equilibrium; Future; HIV; HIV Antigens; HIV Infections; Human immunodeficiency virus test; Immune; Immune system; Immunoglobulin G; In Vitro; Individual; Infection; Lead; Life; Literature; Modeling; Modernization; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Population; Pre-Clinical Model; Publications; Reporting; Residual state; Resistance; Resource-limited setting; Shock; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Viral; Viral reservoir; Viremia; Virus; amphiphilicity; antagonist; antibody conjugate; base; clinically translatable; design; experimental study; improved; in vitro Model; in vivo; latent HIV reservoir; memory CD4 T lymphocyte; nanoGold; nanoparticle; neoplastic cell; neutralizing antibody; novel therapeutics; side effect; targeted delivery

Project Abstract Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, these expensive medications are not accessible for many individuals, in particular those in resource poor settings. It would therefore be of tremendous value to develop novel therapies that can drive HIV into remission, by which we mean into a state where levels of virus remain low or undetectable even when one stops taking ARV medication. At present, no such therapeutic intervention exists. Recent studies have shown that a type of molecule called BCL-2/BCL-XL antagonists is able to promote the death of HIV-infected cells, which could potentially lead to remission. A concern of these BCL-2/BCL-XL antagonists, however, is that they are associated with side-effects that are likely to be considered unacceptable. Relatedly, these molecules are not highly specific to HIV-infected cells and can also cause the death of some uninfected 'bystander' cells. We have developed a technology that allows for the selective targeting of drug-loaded gold nanoparticles to certain cell populations in vivo. In the current proposal we aim to use this technology to more selectively target BCL-2/BCL-XL antagonists to infected cell populations. In Aim 2, this targeting will be relatively broad – for example, targeting all memory CD4+ T-cells. In Aim 3, we will test approaches to specifically target delivery to only HIV infected cells. For both of these approaches 'latency reversing agents (LRAs)' may also be needed to induce some expression of HIV and promote the death of infected cells. In Aim 2, these LRAs will be provided along with BCL-2/BCL-XL antagonist be co-loading gold nanoparticles. In Aim 3, LRAs will be provided first in order to induce HIV expression, allowing subsequent specific targeting of BCL-2/BCL-XL antagonists to HIV-infected cells. Our proposal will take both of these complementary approaches from in vitro experiments through to an in vivo preclinical model. Our ultimate objective is to observe efficacy of the novel therapeutics developed by this project in these preclinical models. If observed, this would enable future clinical trials of these new therapies in people living with HIV, and potentially leading to viral remission without the need for ongoing ARV therapy.

项目摘要 尽管现代疗法极大地改善了人们的生活前景 患有艾滋病毒的人无法治愈感染，使这些人背负着沉重的负担 对于任何特定个人而言，终身致力于抗逆转录病毒 (ARV) 药物治疗。 维持终生坚持用药可能会带来巨大的挑战。 此外，这些昂贵的药物对于许多人来说是无法获得的， 因此，对于那些资源贫乏地区的人来说，这将具有巨大的价值。 开发可以使艾滋病毒缓解的新疗法，我们的意思是进入一种状态 即使停止服用抗逆转录病毒药物，病毒水平仍然很低或无法检测到 目前，尚无此类治疗干预措施。 研究表明，一种称为 BCL-2/BCL-XL 拮抗剂的分子能够促进 HIV感染细胞的死亡，这可能会导致缓解。 然而，BCL-2/BCL-XL 拮抗剂的副作用是： 相关地，这些分子可能被认为是不可接受的。 特定于感染艾滋病毒的细胞，也可能导致一些未感染的细胞死亡 我们开发了一种可以选择性靶向的技术。 目前，载药金纳米粒子对体内某些细胞群的影响。 建议我们的目标是使用该技术更有选择性地靶向 BCL-2/BCL-XL 在目标 2 中，这种目标将相对广泛 – 例如，在目标 3 中，我们将测试针对所有记忆 CD4+ T 细胞的方法。 对于这两种方法，都专门针对 HIV 感染细胞进行递送。 可能还需要“潜伏期逆转剂（LRA）”来诱导 HIV 的某些表达 并促进受感染细胞的死亡，这些 LRA 将与一起提供。 BCL-2/BCL-XL 拮抗剂将共同负载金纳米粒子 在目标 3 中，LRAs 将被共同负载。 首先提供以诱导 HIV 表达，从而允许随后的特定靶向 我们的建议将采用这两种药物来对抗 HIV 感染的细胞。 从体外实验到体内临床前的补充方法 我们的最终目标是观察所开发的新型疗法的功效。 如果观察到该项目在这些临床前模型中的作用，这将使未来的临床成为可能。 这些新疗法在艾滋病毒感染者身上进行的试验，可能会导致病毒感染 无需持续的 ARV 治疗即可缓解。