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