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Impact of drugs of abuse on HIV brain reservoirs and HAND in humanized microglia mice

滥用药物对人源化小胶质细胞小鼠的 HIV 脑库和 HAND 的影响

基本信息

批准号：
10613982
负责人：
Santhi Gorantla
金额：
$ 53.88万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613982
关键词：
Acceleration Acute Affect Aging Animal Model Animals Area Astrocytes Behavior Behavioral Binding Blood Blood Cells Blood Vessels Brain Cells Central Nervous System Central Nervous System Diseases Central Nervous System Infections Chimera organism Chronic Cocaine Contracts Development Disease Disease Progression Disease remission Drug abuse Epidemic Evaluation Functional disorder Goals HIV HIV Infections HIV Seropositivity HIV-associated neurocognitive disorder HIV/AIDS Hematopoietic Stem Cell Transplantation Homeostasis Human Human immunodeficiency virus test Image Immune Immune system Immunity Impaired cognition Incidence Infection Infiltration Inflammation Intervention Invaded Investigation Kinetics Link Long-Term Potentiation Macrophage Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Methods Microglia Modeling Mus Neuroglia Neuronal Injury Neurons Neuropathogenesis Opportunistic Infections Outcome Pathogenesis Pathology Peripheral Predisposition Prevalence Productivity Recurrence Reporter Research Research Personnel Residual state Rodent Model Role Severities Substance Use Disorder Substance abuse problem Substance of Abuse Synaptic plasticity Therapeutic Tissue-Specific Gene Expression Viral Viral reservoir Virus Virus Diseases Virus Latency Virus Replication Work abuse liability acute infection animal imaging antiretroviral therapy axon injury cell behavior chronic infection detection assay drug of abuse experience genetic signature human disease humanized mouse imaging modality insight mouse model multimodality nervous system disorder neuroAIDS neurocognitive disorder neuropathology neurophysiology nucleic acid detection reconstitution serial imaging single-cell RNA sequencing skills substance use therapeutic development therapeutic target tool transmission process viral rebound

项目摘要

ABSTRACT Since the start of the HIV/AIDS epidemic, it has been recognized that drug abuse is strongly linked to contracting and transmitting HIV, as well as more severe consequences. Factors influencing the susceptibility and disease progression are still unclear. Viral reservoir establishment occurs early in acute HIV infection and reaches a set point within the first two months of infection, which in turn determines the size of the reservoir in the chronic stage. HIV enters the brain right after infection and replicates in macrophages, microglia, and to a small extent in astrocytes. Increased susceptibility in substance use could affect the size of the central nervous system (CNS) reservoir, which may influence spontaneous virological remission and viral rebound kinetics. CNS viral reservoir size may also determine the HIV- associated neurocognitive disorder (HAND) severity, viral recurrence, and rebound. Until now, there was no means to study the viral dynamics, CNS viral invasion, susceptibility to MP infection in the brain, and the reservoirs of HIV infection so that interventions can be developed effectively. A small animal model, like the humanized mouse, provides great advantages due to manipulations using host/human cells, as well as the possibility of establishing chronic infection by HIV itself. The humanized microglial (hMGL) mouse model is reconstituted with the human immune system and human glial cells, which allows natural progression of CNS infection and disease in relation to peripheral HIV infection. Herein, we propose to deploy our hMGL mouse to elucidate the mechanisms of HIV-1 invasion, persistence, and neuropathogenesis for substance use. Our objective is to define the CNS viral reservoir and investigate changes in the brain viral reservoir as a consequence of substances of abuse with an overarching goal of viral eradication. Our aims are, 1. to investigate the effect of cocaine on the CNS viral invasion, reservoir establishment, and viral latency during chronic infection in humanized microglial mice, 2. to determine the host genetic signatures that accelerate the CNS viral reservoir and assess the influence of antiretroviral therapy (ART) on glial homeostasis, and 3. to study HIV and SUD-induced neuropathology using a multimodal approach. The complete characterization of this humanized mouse model in establishing linkages to human disease, and demonstrating a comprehensive evaluation of the CNS reservoir during cART, HIV infection, and drug abuse will prove to be a significant value to the neuroHIV field.

摘要

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

感染艾滋病毒的小鼠对可卡因的消退作用受损，并伴有外周和中枢免疫失调。

DOI：
10.21203/rs.3.rs-3276379/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Barker,Jacqueline;Buck,Lauren;Xie,Qiaowei;Willis,Michelle;Side,Christine;Giacometti,Laura;Gaskill,Peter;Park,Kyewon;Shaheen,Farida;Guo,Lili;Gorantla,Santhi
通讯作者：
Gorantla,Santhi