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Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain

在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症

基本信息

批准号：
10458060
负责人：
Schahram Akbarian
金额：
$ 74.35万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458060
关键词：
3-Dimensional AIDS/HIV problem Affect Agonist Anti-Inflammatory Agents Antiinflammatory Effect Autopsy Award Behavior Biological Models Brain CD34 gene CD8B1 gene CNR1 gene CNR2 gene Cells Chromatin Cocaine Abuse Cognition Complement Data Diagnosis Disease DsRed Encephalitis Enterobacteria phage P1 Cre recombinase Epidemic Funding Gene Expression Genes Genetic Recombination Genome Genomics HIV HIV Genome HIV Infections HIV encephalitis HIV-associated neurocognitive disorder Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hi-C High Prevalence Human Immune system Immunodeficient Mouse Infection Inflammation Injections Intervention Investigational Therapies Knock-in Laboratories Link Liver Macrophage Colony-Stimulating Factor Maps Measures Mediating Microglia Modeling Molecular Conformation Molecular Profiling Mus Neonatal Neurobiology Neuroglia Pattern Peripheral Persons Pharmaceutical Preparations Primary Cell Cultures RNA Regimen Reporter Rewards Site Specimen Substance Use Disorder Switch Genes System Technology Testing Time Tissues Transcript Transplantation Treatment Protocols Umbilical Cord Blood Variant Viral Work addiction antiretroviral therapy base cannabinoid receptor cell type cognitive function epigenome epigenomics improved induced pluripotent stem cell integration site latent infection macrophage mouse model neonatal mice neuroAIDS neurogenomics neuroinflammation novel opioid abuse preference progenitor reconstitution transcriptome transcriptome sequencing transcriptomics

项目摘要

HIV-associated neurocognitive disorders persist in the era of combination antiretroviral therapy (cART) while HIV latency, and cell-specific expression of HIV transcript in human CNS remains incompletely understood. There is high prevalence of HIV-associated neurologic disease and increasing recognition of CNS viral escape in people stably suppressed with cART, often further complicated by the co-registered epidemic of substance use disorders (SUD) in people living with HIV/AIDS (PLWHA), as SUD also have profound impact on CNS function. Ongoing work in our laboratory is providing first assessments of cell-type specific HIV 'molecular signatures', including genome integration patterns and alterations on the level of the transcriptome and epigenome in reward- and addiction circuitry of the human postmortem brain. As described in detail in the Preliminary Data section, we found dramatically high levels of HIV expression in a subset of microglia from postmortem specimens, with HIV transcript levels ranking among the top 5 highest expressed RNAs in microglia, or the 99.9% percentile of all microglial transcript. Correspondingly, HIV genome integration sites in addiction circuitry are dominated by microglia-specific genes, with strong preference for active chromatin compartments. However, lingering effects of latent infection that persist during cART have not been well characterized—in part because of fundamental challenges in identifying the extent to which microglial cells contribute to the latent reservoir. Our preliminary studies also provide a model system whereby we can track and isolate persistently infected cells which can be applied to the microglial compartment and will allow us to define the genomic perturbations that persist during cART. By studying HIV genomics in human microglia residing in the mouse brain and linking this with technology to track persistently infected microglia, we will be able to model, for the first time, experimental therapies and interventions to complement our descriptive work in human postmortem brain. Specifically, our Cre-reporter based HIV-induced lineage tracing (HILT) marking system will allow us to quantify and isolate the rare latently infected microglia that persist during cART, and map transcriptomic and epigenomic alterations separately both for infected, and non-infected microglia, both collected from the same mouse brain. With focus on addition circuitry, we will study neuroinflammation, cognition and reward behavior in mice treated with standard cART regimens and an experimental therapy involving Cannabinoid receptor 2 agonist drugs that, according to our preliminary data, are linked to anti-inflammatory activity limiting the extent of HIV infection in tissues.

hiv相关的神经认知障碍在抗逆转录病毒联合治疗的时代仍然存在