Characterizing Vpr-mediated Activation of the DNA Damage Response (DDR) in HIV Replication
HIV 复制中 Vpr 介导的 DNA 损伤反应 (DDR) 激活的特征
基本信息
- 批准号:10613920
- 负责人:
- 金额:--
- 依托单位:
- 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:2022-07-01 至 2023-07-02
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeBIRC3 geneBiological AssayBiologyCell Cycle ArrestCellsCollaborationsComet AssayComplexConsequences of HIVDNA DamageDNA Replication DamageDNA VirusesDataDendritic CellsDevelopmentGenesGenetic TranscriptionGenomeGoalsHIVHIV InfectionsHIV-1HIV-2IL8 geneImmuneImmunofluorescence ImmunologicInfectionKnock-outKnowledgeLentivirusLettersLife Cycle StagesLinkM cellMacrophageMediatingMolecularMolecular BiologyMutation AnalysisNBS1 geneNF-kappa BNatural ImmunityNuclearPathway interactionsPersonsPhenotypePrimate LentivirusesQuantitative Reverse Transcriptase PCRRNA VirusesRepressionResearchRoleScientistSignal PathwaySignal TransductionTestingUp-RegulationViralVirusVirus ReplicationVirus-like particleantiretroviral therapyassaultgenotoxicityglobal healthimprovedin vivoinhibitorinsightknock-downlive cell imagingmonocytenovelp53-binding protein 1p65recruitresponsesuccesstranscriptome sequencingtumorigenesisvpr Gene Products
项目摘要
PROJECT SUMMARY
HIV continues to be a major burden to global health as it accounts for approximately 36.9 million people living
with acquired immunodeficiency syndrome (AIDS). Scientists have made considerable strides in understanding
the basic molecular biology of HIV, which directly led to the development of effective antiretroviral therapy (ART).
Yet, despite years of research, we currently do not have a complete picture of the HIV lifecycle to help develop
a functional cure. By understanding key steps in the HIV lifecycle and establishing the cellular consequences of
HIV infection, we can develop novel treatments and a functional cure, which take advantage of the cellular
markers that HIV infection leaves behind. One key aspect of HIV biology that remains unclear is Vpr, an
accessory gene without a known primary conserved function. Vpr is evolutionarily conserved among extant
primate lentiviruses and is required for virus replication in vivo. Although Vpr enhances viral replication in
monocyte-derived macrophages and monocyte-derived dendritic cells, it remains unclear how Vpr enhances
replication. An emerging phenotype described for Vpr is engagement with the DNA damage response (DDR).
The DDR is a signaling cascade responsible for safeguarding the genome from genotoxic assault that is well
understood. Modulation of the DDR is often seen by diverse RNA and DNA viruses to promote tumorigenesis or
enhancement of viral replication. Most interestingly, we found that Vpr can induce DNA damage and the ability
of Vpr to induce DNA damage is conserved among HIV-1 and HIV-2. In addition, activation of the DDR is linked
to NF-kB and innate immunity. Our preliminary data suggest that Vpr-induced DNA damage activates NF-kB.
This data contributes to our central hypothesis that Vpr-induced DNA damage signals through the classical
DDR to activate NF-kB target genes and enhance viral replication.
In this proposal, we will investigate how and why Vpr induces DNA damage. In Aim 1, I will characterize the
requirements and downstream signaling of Vpr-induced DNA damage. Completing this aim will shed light on
how Vpr induces DNA damage and establishes if the classical DDR is activated or if non-classical activation
mechanisms await to be explored. In Aim 2, I will identify the role of Vpr-induced DNA damage activation of NF-
κB target genes in HIV replication. Completing this aim will determine why Vpr causes DNA damage and will
establish the molecular mechanism for Vpr-enhancement of viral replication. Overall, we will gain insight into
how HIV infected cells are dealing with DNA damage. The long-term goal is to leverage our understanding of
DNA damage in HIV infected cells to develop improved treatments and a functional cure for people with
HIV/AIDS.
项目总结
项目成果
期刊论文数量(0)
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Carina Sandoval其他文献
Carina Sandoval的其他文献
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{{ truncateString('Carina Sandoval', 18)}}的其他基金
Characterizing Vpr-mediated Activation of the DNA Damage Response (DDR) in HIV Replication
HIV 复制中 Vpr 介导的 DNA 损伤反应 (DDR) 激活的特征
- 批准号:
10483976 - 财政年份:2022
- 资助金额:
-- - 项目类别: