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: 10207378
• 负责人: Darrell J Irvine
• 金额: $ 78.42万
• 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/10207378
• 关键词: Adherence; Anti-Retroviral Agents; Antigen Targeting; Apoptosis; BCL1 Oncogene; BCL2 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; Resources; Shock; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Viral; Viral reservoir; Viremia; Virus; amphiphilicity; 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; Adherence; Anti-Retroviral Agents; Antigen Targeting; Apoptosis; BCL1 Oncogene; BCL2 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; Resources; Shock; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Viral; Viral reservoir; Viremia; Virus; amphiphilicity; 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生活的人们的前景 与艾滋病毒一起，他们无法治愈感染，使这些人烧毁了 终身对抗逆转录病毒（ARV）药物的承诺。对于任何给定的人， 维持终身遵守药物可能会带来重大挑战。 此外，这些昂贵的药物对于许多人无法使用 特别是在资源不良的设置中。因此，这将具有巨大的价值 开发新的疗法，可以将艾滋病毒推向缓解，我们的意思是 即使停止服用ARV，病毒水平仍然保持低或无法检测 药物。目前，尚无这种治疗干预措施。最近的研究 表明一种称为Bcl-2/bcl-XL拮抗剂的分子能够促进 HIV感染细胞的死亡可能导致缓解。这些关注 但是，bcl-2/bcl-xl拮抗剂是它们与副作用相关的 可能被认为是不可接受的。相关，这些分子不高 特定于感染HIV的细胞，也可能导致一些未感染的死亡 “旁观者”细胞。我们开发了一种允许选择性定位的技术 在体内对某些细胞群体的药物负载的金纳米颗粒的大量。在电流中 提案我们旨在使用这项技术更有选择地针对BCL-2/BCL-XL 对感染细胞群体的拮抗剂。在AIM 2中，此目标将相对广泛 - 例如，针对所有内存CD4+ T细胞。在AIM 3中，我们将测试方法 专门针对仅针对感染HIV感染的细胞的递送。对于这两种方法 也可能需要“延迟逆转剂（LRA）”来诱导艾滋病毒的某些表达 并促进感染细胞的死亡。在AIM 2中，将提供这些LRA Bcl-2/bcl-XL拮抗剂是共同加载金纳米颗粒。在AIM 3中，LRA将会 首先提供的目的是诱导艾滋病毒表达，允许随后的特定靶向 Bcl-2/bcl-XL对HIV感染细胞的拮抗剂。我们的提议将两者都接受 从体外实验到体内临床前的完全接近 模型。我们的最终目标是观察开发新疗法的效率 这些项目在这些临床前模型中。如果观察到，这将使未来的临床 对艾滋病毒感染者的这些新疗法的试验，并有可能导致病毒 缓解无需持续的ARV治疗。