Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control
Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control
批准号:
10748561
负责人:
Dianne Teresa LANGFORD
金额:
$23.78万
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:
2023-08-05 至 2025-07-31
关键词:
AddressBiological AssayBrainCell LineCellsCentral Nervous SystemChromatinChromatin Remodeling FactorCo-ImmunoprecipitationsComplexDataDevelopmentDisease remissionEnsureEnvironmentEnzymesEpigenetic ProcessEventExhibitsFunctional disorderFutureHIVHIV InfectionsHIV-1HIV-associated neurocognitive disorderHealthHeterochromatinHistone DeacetylaseHumanImmune responseImpairmentIn VitroInfectionInnate Immune ResponseInterferonsLongevityLysineMediatingMethyltransferaseMicrogliaModelingNeurogliaPathogenesisPathway interactionsPatternPeptide HydrolasesPersonsPhosphorylationPluripotent Stem CellsPost-Translational Protein ProcessingProcessProductivityProteinsProteomeProteomicsRegulationResearchRoleSUMO1 geneShockSignal TransductionSiteSmall Ubiquitin-Related Modifier ProteinsSourceSumoylation PathwaySystemT-LymphocyteTRIM MotifTestingTimeUbiquitinUbiquitinationViralViral Load resultViral PathogenesisViral reservoirVirusVirus DiseasesVirus LatencyVirus ReplicationWorkWrestlingadductantiretroviral therapyantiviral immunitycell typechicken ovalbumin upstream promoter-transcription factorgenetic corepressorhuman modelinsightmutantnovelparalogous geneparticlepathogenpreventpromoterprotein protein interactionrecruitrestorationsuccesstherapeutic developmenttranscription factorubiquitin ligaseubiquitin-protein ligase
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
This project will explore strategies to target epigenetic pathways for achieving sustained HIV remission
and treatment of HIV associated-central nervous system (CNS) dysfunction. The conjugation of small ubiquitin-
SUMO proteins to substrates is a well-described post-translational modification that regulates protein activity,
subcellular localization, and protein-protein interactions for various downstream activities. SUMO proteins are
also important in anti-viral immunity, opposing viral replication and mediating interferon-dependent anti-viral
mechanisms. Thus, pathogens have evolved to exploit the host SUMOylation machinery to ensure viral
persistence and pathogenesis. During infection, the human immunodeficiency virus type 1 (HIV-1) manipulates
the host SUMOylation machinery to ensure its viral replication in CD4+
manipulates
Microglia
T cells, however, whether HIV-1
the SUMO paralogs to control its replication and/or atency in glial cells like microglia is unclear.
are the main HIV-1 target cells in the CNS and constitute an important reservoir for viral pathogenesis.
l
In microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multi-enzymatic chromatin-
modifying complex and establishes a heterochromatic environment at the HIV-1 promoter, leading to HIV-1
silencing. Studies have shown that post-translational modifications (PTMs), including phosphorylation and
SUMOylation, mediate CTIP2's interactions with other proteins and complexes. Similarly, tripartite motif-
containing protein 28 (TRIM28), a known SUMO E3 ligase, associates with CTIP2 in the heterochromatin
complex to inhibit HIV-1 viral replication. While
regulating
respectively,
unknown.
productive
SUMOylation
inducible
SUMOylation and phosphorylation have been implicated in
the activity of CTIP2 and TRIM28 in the context of T-cell signaling events and immune responses,
the impact of PTMs in the initiation and establishment of HIV-1 latency in microglia remains
To this end, this proposal's central hypothesis is that the host SUMOylation system is i mpaired during
HIV-1 infection in microglia and that latency is established as a result of the estoration of
of host proteins. To test this hypothesis , we will use immortalized human microglial cell lines and
pluripotent stem cells (iPSCs), including a novel model of HIV-1 latency.
r
We will also identify the
SUMO-modified proteome of human microglial cells during human HIV-1 infection.
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会议论文
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海外基金