Defining the impact of cannabinoids on the HIV reservoir in humanized mice
Defining the impact of cannabinoids on the HIV reservoir in humanized mice
批准号:
10814024
负责人:
Edward P Browne
金额:
$53.47万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-30 至 2025-07-31
关键词:
ATAC-seqAcuteAddressAffectAgonistAnimal ModelAnti-Inflammatory AgentsBiological AssayBiologyBloodBrainCD4 Positive T LymphocytesCannabinoidsCannabisCellsCharacteristicsChronicClinicalDataDoseEffector CellEventExhibitsExposure toGenetic TranscriptionGoalsHIVHIV InfectionsHeterogeneityHomeostasisHumanImmuneImmune responseImmune systemImmunityImmunologic MarkersImmunologicsIndividualInfectionInflammationInflammatoryLearningMaintenanceMediatingMethodsMicrogliaModelingMolecularMusNF-kappa BNatural Killer CellsOutcomeParticipantPathway interactionsPeripheralPersonsPhasePhenotypePopulationResearchSignal InductionSignal PathwaySolidSpleenT-LymphocyteTHC exposureTestingTissue SampleTissuesViralViral PhysiologyViral reservoirViremiaVirus LatencyWorkantiretroviral therapybrain tissuecannabinoid receptorcytokineexhaustionhuman datahuman tissuehumanized mouseimmunoregulationin vivoinnovationinsightlatent HIV reservoirlongitudinal human studymarijuana usemarijuana usermolecular phenotypemouse modelneuroprotectionnovelperipheral bloodpolysubstance usereconstitutionsenescencesingle cell analysistooltranscriptome sequencingviral DNAviral RNA
中文摘要
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英文摘要
Abstract
Cannabis (CB) use is prevalent amongst people with HIV (PWH) but its impact on HIV infection and the latent
viral reservoir has not been fully examined. In particular, the impact of CB on the HIV reservoir in solid tissues
such as the brain is completely unknown. As such, animal models in which dosing can be carefully controlled
and tissue samples can be analyzed will be important to fully understand how CB impacts HIV reservoir
characteristics in tissues. Our central hypothesis is that CB induces an immunosuppressive cellular state that
impacts viral transcription and maintenance of the HIV reservoir in tissues. The overall goal of this proposal is
to develop a humanized mouse model of CB exposure during HIV infection and to use this model to learn how
CB use affects characteristics of the tissue resident HIV reservoir. In the R61 phase, HIV infected humanized
mice expressing hIL-34 to promote microglial CNS reconstitution will be exposed to a range of THC doses
during infection, both before and after viral suppression with antiretroviral therapy (ART). The impact of THC
exposure on viremia, viral suppression, immune markers and cytokines in peripheral blood will be examined.
In the R33 phase, we will use this model to address three major questions. First, viral DNA (vDNA) and viral
RNA (vRNA) levels in the brains and spleens of infected mice that have been dosed with THC will be
quantified to determine the impact of THC on the size and transcriptional activity of the viral reservoir in these
tissues. Second, we will examine whether THC exposure affects HIV latency reversal in vivo. We hypothesize
that cross-talk between inflammatory signaling pathways activated by potent latency reversing agents (LRAs)
such as the non-canonical NF-kB agonist AZD5582 and anti-inflammatory pathways activated by CB use could
significantly alter the outcome of LRA dosing in vivo. To test this hypothesis, THC or control exposed HIV
infected mice will be dosed with AZD5582, and the impact of THC on viremia and viral reactivation in tissues
will be examined. Finally, we will use this model to perform a deep single cell characterization of infected cells
in the brains and spleens of ART-suppressed humanized mice in the presence and absence of THC exposure.
Spleen and brain tissues will be profiled using a combined single cell ATACseq/RNAseq method to identify and
characterize HIV vDNA+ or vRNA+ cells and to compare the abundance and phenotype of these cells between
CB dosed mice and controls. If successful, this proposal will reveal new insights into how CB affects HIV
infection and the characteristics of the tissue-resident HIV reservoir. This in turn will guide novel HIV cure
strategies that are optimized for CB-using PWH.
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会议论文
Understanding HIV reservoir formation by profiling transcriptomic and epigenetic changes in CD4 T cells following ART initiation
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批准号:10759940
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项目类别:
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资助金额:$27.21万
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财政年份:2023
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负责人:Edward P Browne
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依托单位:
Defining the impact of cannabinoids on the latent HIV reservoir through multi-omic analysis
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批准号:10219556
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项目类别:
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资助金额:$67.15万
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财政年份:2021
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负责人:Edward P Browne
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依托单位:
Defining the impact of cannabinoids on the latent HIV reservoir through multi-omic analysis
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批准号:10622522
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项目类别:
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资助金额:$66.42万
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财政年份:2021
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负责人:Edward P Browne
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依托单位:
Defining the impact of cannabinoids on the latent HIV reservoir through multi-omic analysis
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批准号:10433912
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项目类别:
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资助金额:$65.95万
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财政年份:2021
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负责人:Edward P Browne
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依托单位:
Regulation of HIV Latency by Host Cell Transcriptional and Epigenetic Networks
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批准号:10202457
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项目类别:
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资助金额:$38.88万
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财政年份:2019
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负责人:Edward P Browne
-
依托单位:
Regulation of HIV Latency by Host Cell Transcriptional and Epigenetic Networks
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批准号:9978705
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项目类别:
-
资助金额:$38.88万
-
财政年份:2019
-
负责人:Edward P Browne
-
依托单位:
Regulation of HIV Latency by Host Cell Transcriptional and Epigenetic Networks
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批准号:10425316
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项目类别:
-
资助金额:$38.88万
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财政年份:2019
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负责人:Edward P Browne
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依托单位:
海外基金