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Defining the impact of cannabinoids on the latent HIV reservoir through multi-omic analysis

通过多组学分析确定大麻素对潜在 HIV 储存库的影响

基本信息

批准号：
10622522
负责人：
Edward P Browne
金额：
$ 66.42万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2021-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10622522
关键词：
Anti-Inflammatory Agents Biological Assay Biological Models Blood specimen CD4 Positive T Lymphocytes CNR2 gene Cannabinoids Cell model Cells Cellular Assay Characteristics Chromatin Structure Chronic Clinical Collection DNA Data Data Set Gene Expression Gene Expression Profile Genetic Transcription Genomics Goals HIV HIV Infections Immune In Vitro Individual Investigation Location Maintenance Methods Modeling Molecular Nature Outcome Pathway interactions Peripheral Blood Mononuclear Cell Persons Phase Phenotype Population Property Proviruses Role Sampling Shapes Signal Induction Signal Pathway Signal Transduction T-Lymphocyte Testing Time Transcript Transcription Factor AP-1 Viral Viral Genes Viral reservoir cohort data integration design drug of abuse epigenome epigenomics immunoregulation in vivo insight latent HIV reservoir multiple omics novel reactivation from latency tool transcriptome transcriptomics

项目摘要

Project summary The latent reservoir is the primary barrier to curing HIV, but little is known about the nature of this reservoir or the molecular mechanisms that regulate it. Increasing evidence suggests that the size and nature of this reservoir is impacted by drugs of abuse. Cannabinoid (CB) abuse, in particular, is prevalent amongst people with HIV (PWH), but the impact of CBs on the latent HIV reservoir has not been investigated. CBs are known to have immuno-modulatory and anti-inflammatory activities through activation of the CB2 receptor that is widely expressed in immune cells, including CD4 T cells. Our hypothesis is that CB exposure during HIV infection alters the size, location and transcriptomic phenotype of the latent HIV reservoir through CB2-dependent activation of the AP-1 transcription factor in CD4 T cells. Consistent with this hypothesis we have recently discovered that cannabinoids promote reactivation of HIV from latency in a T cell model. Defining the impact of CBs on the latent HIV reservoir will be critical to designing appropriate approaches to clear the reservoir from PWH who use CBs. To achieve this goal we propose to use cutting edge methods from the fields of single cell multi-omic analysis to characterize the effect of CBs on the latent HIV reservoir, and to test the functional role of CB-activated pathways in HIV latency. In the R61 phase, we will use a primary cell HIV latency model to define the impact of CB exposure on the transcriptome and epigenome of latently infected cells. Additionally, we will use a cutting-edge single cell HIV assay to quantify the size and location of the intact HIV reservoir in a cohort of CB-using PWH compared to non CB-using PWH. For the R33 phase, we will combine the results from these studies with a detailed single cell genomic analysis of identify CB-regulated transcripts in the PBMCs and CD4 T cells from the CB-using PWH cohort. By integrating these datasets we aim to identify CB-regulated pathways that regulate the size and subcellular location of the HIV reservoir. Overall these results will advance our understanding of how CBs interact with the latent HIV reservoir at the molecular level.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Machine learning approaches identify immunologic signatures of total and intact HIV DNA during long-term antiretroviral therapy.

机器学习方法可识别长期抗逆转录病毒治疗期间完整且完整的 HIV DNA 的免疫学特征。

DOI：
10.1101/2023.11.16.567386
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Semenova,Lesia;Wang,Yingfan;Falcinelli,Shane;Archin,Nancie;Cooper-Volkheimer,AliciaD;Margolis,DavidM;Goonetilleke,Nilu;Murdoch,DavidM;Rudin,CynthiaD;Browne,EdwardP
通讯作者：
Browne,EdwardP

The Rashomon Importance Distribution: Getting RID of Unstable, Single Model-based Variable Importance

DOI：
10.48550/arxiv.2309.13775
发表时间：
2023-09
期刊：
ArXiv
影响因子：
0
作者：
J. Donnelly;Srikar Katta;C. Rudin;E. Browne
通讯作者：
J. Donnelly;Srikar Katta;C. Rudin;E. Browne

Automated microarray for single-cell sorting and collection of lymphocytes following HIV reactivation.

用于 HIV 重新激活后的单细胞分选和淋巴细胞收集的自动化微阵列。

DOI：
10.1101/2023.02.02.526757
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Cortés-Llanos,Belén;Jain,Vaibhav;Volkheimer,Alicia;Browne,EdwardP;Murdoch,DavidM;Allbritton,NancyL
通讯作者：
Allbritton,NancyL

Towards a comprehensive evaluation of dimension reduction methods for transcriptomic data visualization.

DOI：
10.1038/s42003-022-03628-x
发表时间：
2022-07-19
期刊：
Communications biology
影响因子：
5.9
作者：
通讯作者：

New Concepts in Therapeutic Manipulation of HIV-1 Transcription and Latency: Latency Reversal versus Latency Prevention.

DOI：
10.3390/v15081677
发表时间：
2023-07-31
期刊：
Viruses
影响因子：
0
作者：
Lewis CA;Margolis DM;Browne EP
通讯作者：
Browne EP

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Edward P Browne其他文献

Virus-host interactions: new insights from the small RNA world

DOI：
10.1186/gb-2005-6-11-238
发表时间：
2005-01-01
期刊：
GENOME BIOLOGY
影响因子：
9.400
作者：
Edward P Browne;Junjie Li;Mark Chong;Dan R Littman
通讯作者：
Dan R Littman

PP 4.24 – 00176 Impact of cannabis use on immune cell populations and the viral reservoir in HIV-infected people on suppressive antiretroviral therapy

DOI：
10.1016/j.jve.2022.100232
发表时间：
2022-12-01
期刊：
Conference abstract
影响因子：
作者：
Shane D. Falcinelli;Alicia Volkheimer;Lesia Semenova;Ethan Wu;Alexander Richardson;Manickam Ashokkumar;David M Margolis;Nancie M. Archin;Cynthia D Rudin;David Murdoch;Edward P Browne
通讯作者：
Edward P Browne