Next-generation extracellular vesicle biologics to target central nervous system and peripheral reservoirs of HIV

针对中枢神经系统和外周 HIV 储存库的下一代细胞外囊泡生物制剂

• 批准号: 10594056
• 负责人: Bharat Ramratnam
• 金额: $ 77.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594056
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Astrocytes; Binding; Biodistribution; Biological; Biological Assay; Biological Markers; Biological Products; Blood - brain barrier anatomy; Blood Cells; Brain; CD4 Positive T Lymphocytes; Cells; Central Nervous System; Central Nervous System Diseases; Cerebrospinal Fluid; Chemistry; DNA; Data; Development; Disease; Dose; Engineering; Event; Female; Funding; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Health; Heart Diseases; In Vitro; Infection; Inflammation; Inflammatory Response; Intravenous; Length; Lipids; Macaca; Macrophage; Malignant Neoplasms; Measurement; Measures; Membrane; Microdissection; Microglia; Modeling; Monitor; Morbidity - disease rate; Neurons; Parents; Pathogenesis; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Plasma; Primates; Process; Production; Proteins; RNA; RNA Splicing; Reporter; Retroviridae; SIV; Sampling; Small RNA; Specificity; Spleen; Surface; System; Testing; Therapeutic; Tissues; Toxic effect; Tracer; Trans-Activators; Transcription Coactivator; Viral; Viral reservoir; antiretroviral therapy; cell type; cytokine; experience; experimental study; extracellular vesicles; improved; in vivo evaluation; innovation; intercellular communication; lymph nodes; male; monocyte; mortality; multidisciplinary; neurocognitive disorder; next generation; nonhuman primate; novel; particle; timeline; tool; transmission process; treatment response; viral RNA; viral rebound

Abstract In the era of combined antiretroviral therapy (cART), mortality and morbidity associated with HIV-1 infection has been reduced. Nevertheless, a wide range of AIDS-related conditions as well as serious non-AIDS events (SNAEs) continue to afflict people living with HIV (PLWH). Improved long-term strategies are needed, ranging from easier administration to better suppression to functional cure. Barriers to functional cure include a limited ability to deliver activators and other bioactive molecules into tissue reservoirs of HIV, particularly the possible reservoirs in the central nervous system (CNS). Representing a novel mode of delivery, extracellular vesicles (EVs) are double membrane-bound particles, released by all known cell types, that engage in intercellular communication by shuttling components of the parent cell (such as proteins and RNAs) to target cells. EVs contribute to disease pathogenesis and are actively investigated, especially in cancers, as biomarkers, actors in disease processes, and potential therapeutics. Importantly, EVs have been shown to cross biological barriers, even the blood-brain barrier, and can be easily delivered to the brain. EVs thus provide an exceptional opportunity to deliver components of HIV control or reactivation/cure to tissue reservoirs, with potential for cell-specificity. To this end, we have assembled a multidisciplinary team with two major, unique assets. The first is a novel small EV-transcriptional activator (sEVTA) tool that has already passed in vitro and in vivo tests. In this system, retroviral transactivator proteins are specifically packaged into EVs, which can be further functionalized with tracers and surface peptides for cell targeting. The second is our well established SIV/macaque model, which has been used successfully to study retroviral latency, rebound, and retrovirus-associated CNS disease. We will conduct careful nonhuman primate dosing and distribution studies followed by optimized intravenous and intranasal delivery of sEVTAs. Effects of sEVTAs on viral rebound will be assessed with innovative tools in circulating and peripheral tissue reservoirs (Aim 1), followed by reservoirs in the CNS (Aim 2). In Aim 3, we will investigate the potential toxicity of these approaches, with particular focus on the central nervous system, and explore more cell-targeted approaches. The goal of these studies is to use sEVTAs to reactivate latent retroviruses in the CNS and the periphery. However, the project will also provide much-needed information about EV delivery, distribution, and efficacy in primates that can be harnessed in development of a variety of therapies for HIV infection and disease.

摘要