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Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations

苯二氮卓介导离散骨髓细胞群转录半静止机制

基本信息

批准号：
10573380
负责人：
Peter Jesse Gaskill
金额：
$ 69.51万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573380
关键词：
Address Affect American Anatomy Atlases Awareness Benzodiazepines Brain Cells Chromatin Clinical Complex DNA Data Data Correlations Development Disease Dose Epigenetic Process Failure Gene Expression Profile Genetic Genetic Transcription HIV HIV Infections HIV-1 Human Image Individual Infection Infection prevention Mediating Microglia Myelogenous Myeloid Cells Neuraxis Neurocognitive Neuropathogenesis Outcome Penetrance Persons Pharmaceutical Preparations Population Process Production Protocols documentation Proviruses Publishing RUNX1 gene Recrudescences Regulation Risk Role Small Interfering RNA Source Substance Use Disorder Symptoms Testing Therapeutic Transcription Process Transcriptional Regulation Viral Viral reservoir Virion Virus Virus Replication Vulnerable Populations Xanax abuse liability antiretroviral therapy benzodiazepine misuse cell type chromatin immunoprecipitation chronic infection drug misuse epigenetic regulation gag Gene Products induced pluripotent stem cell knock-down macrophage memory CD4 T lymphocyte monocyte mutant neuroAIDS neuroinflammation novel therapeutics programs reactivation from latency recruit reduce symptoms viral DNA viral RNA

项目摘要

One of the principal obstacles to curing HIV is the existence of viral reservoirs in distinct compartments and cell types that are unaffected by antiretroviral therapy (ART). In the central nervous system (CNS), these reservoirs are comprised of myeloid cells, such as perivascular macrophages and microglia. Critically, these reservoirs are generally established prior to the initiation of ART and the presence of ART in the CNS does not affect the established reservoir in long-lived myeloid populations. Thus, even in individuals on suppressive ART, persistently infected CNS macrophages and microglia can drive ongoing neuroinflammation and provide a source of HIV for viral recrudescence during medication hiatus or failure. Our ability to eliminate these reservoirs is severely limited by the lack of understanding of the transcriptional and epigenetic regulation of HIV in myeloid cells. To effectively target and eliminate CNS reservoirs in people living with HIV (PLWH), it is critical to define the transcriptional mechanisms mediating persistent infection in distinct CNS myeloid populations. The impact of HIV infection in the CNS is heightened in PLWH who have substance use disorders, including those who take and/or misuse therapeutic drugs such as benzodiazepines (BDZ). Benzodiazepines are used by more than 30 million Americans, have high abuse liability and misuse of these drugs accounts for 15 – 20% of their use. Benzodiazepines are prescribed to a growing number of PLWH and are associated with an increased risk of neurocognitive symptoms in this population. Little is known about the mechanisms by which BDZ impact HIV neuropathogenesis. Our published and preliminary data indicate that BDZ can alter the transcriptional regulation of HIV infection. To better understand and treat the development of neuroHIV in PLWH who use and/or misuse BDZ, it is vital to determine who benzodiazepines affect the transcriptional programs in myeloid cells. We hypothesize that both macrophages and microglia enter a semi-quiescent transcriptional state during ART exposure and that benzodiazepines disrupt this state and increase transcriptional activity and viral replication. Our data show that the BDZ Xanax, as well as some latency reactivation agents, mediate a dose-dependent increase in p24 production in infected, ART-treated cells. Our preliminary studies suggest these effects may result from BDZ interactions with the epigenetic regulator RUNX1. We posit that these changes in HIV replication in myeloid cells reflect the epigenetic state of the provirus. Thus, the growing population of PLWH who use BDZ is at greater risk of more severe neuropathogenesis. It also suggests that BDZ may provide the basis for novel therapeutics to manipulate HIV transcription in myeloid cells. Therefore, we will evaluate the transcriptional and epigenetic mechanisms sustaining the semi-quiescent state of HIV transcription in ART- treated human macrophages (Aim 1), define the differences in transcriptional and epigenetic processes in different types of myeloid cells using human syngeneic iPSC-derived macrophages and microglia (Aim 2), and examine the effect of benzodiazepines on transcription HIV-infected, ART-treated myeloid cells (Aim 3).

治疗艾滋病毒的主要障碍之一是存在于不同的隔室和病毒库