Spatiotemporal Staging of the HIV-1 Preintegration complex
HIV-1 预整合复合体的时空分期
基本信息
- 批准号:10548553
- 负责人:
- 金额:$ 65.88万
- 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:2022-05-20 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AIDS/HIV problemAcuteAffectAnti-Retroviral AgentsBiochemicalBiochemistryBiological AssayBiologyCapsidCell NucleusCellsChromosomesComplexCoupledCrude ExtractsCytoplasmDNADNA IntegrationDNA biosynthesisDataDevelopmentDisease ManagementDrug resistanceEnzymesFaceGenomeHIVHIV InfectionsHIV-1HIV-1 integraseHourIn VitroInfectionIntegraseIntegrase InhibitorsIntegration Host FactorsKineticsKnowledgeLifeLinkMeasuresMediatingMetabolicModelingMonitorNuclearNuclear ExtractNuclear Pore ComplexPersonsPharmaceutical PreparationsPlayPositioning AttributeRNAReagentRegimenResearchReverse TranscriptionRoleStagingT-LymphocyteTestingTimeTranscription ProcessViralVirusVirus Integrationantiretroviral therapybasedrug developmentds-DNAimprovedin vitro activityinhibitorinsertion/deletion mutationmutantneuropsychiatrynovelnovel strategiespreservationspatiotemporaltime usetoolviral DNAviral RNA
项目摘要
ABSTRACT
Approximately 1.2 million people in the US and ~40 million people worldwide are infected with HIV. In
spite of significant progress in HIV/AIDS research, anti-retroviral therapy (ART) remains the only treatment
option available for HIV-1 infection. ART has been highly effective in controlling the virus and making HIV
infection a manageable disease. Specifically, inhibitors of HIV-1 Integrase (IN) are used as the preferred drugs
in the current ART regimens. However, these inhibitors continue to face drug resistance and there is growing
concern of the adverse metabolic and neuropsychiatric effects of these inhibitors. Thus, there is a need for the
development of new and improved IN inhibitors for effective and long-term control HIV-1 infection. Such effort
is critically dependent on a better understanding of the mechanisms of HIV-1 integration. It is important to note
that studies of the preintegration complex (PIC) extracted from acutely infected cells have been instrumental in
defining the mechanisms of HIV-1 integration. Furthermore, PIC studies have played a central role in the
development of currently used IN inhibitors. Therefore, our proposal to define the mechanism of HIV-1 PIC
formation will generate new knowledge to promote the development of new and improved IN-based therapies.
Retroviral replication is dependent on the essential steps of reverse transcription (RTN) and integration.
In the case of HIV, the RNA genome is reverse transcribed into a DNA copy by the reverse transcription
complex (RTC). Then, the RTC transitions into a PIC by an unknown mechanism and undefined time. The PIC,
containing the viral DNA, the IN enzyme, and other viral/host factors, carries out integration. The prevailing
view is that HIV-1 RTN is completed in the cytoplasm and/or at the nuclear pore complex (NPC). Thus, nuclear
entry of the PIC is necessary to carry out HIV-1 DNA integration into the host chromosomes. However, new
evidence suggest that the intact HIV-1 capsid enters the nucleus and RTN is completed after the nuclear entry
step. A nuclear completion of RTN creates key knowledge gaps in our current understanding of the PIC. We
hypothesize that functional HIV-1 PICs are formed prior to the completion of RTN and nuclear entry protects
the integrity of the PIC-viral DNA. This proposal will test this hypothesis through three specific aims: Aim 1 will
define the link between the timing of functional PIC formation relative to RTN completion, Aim 2 will assess the
role of nuclear entry on PIC function, and Aim 3 will determine the spatiotemporal transition of the RTC to a
PIC. For these aims, we have developed a novel approach of quantifying PIC-specific integration activity and
measuring HIV-1 core-mediated DNA integration, coupled with the blockade of viral nuclear entry and time of
inhibitor addition assays. Together, these studies will define the mechanistic and kinetic link between HIV-1
RTN and PIC function. Most importantly, our team is uniquely qualified to successfully complete this timely
R01-project, since we have the expertise, reagents, and the tools required to study PIC biochemistry (Dash),
Capsid biology (Aiken), Nuclear entry (Campbell), and Integration (Engelman and Craigie).
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chandravanu Dash其他文献
Chandravanu Dash的其他文献
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{{ truncateString('Chandravanu Dash', 18)}}的其他基金
Role of GRIN2 in ART and SUD associated neurological deficits.
GRIN2 在 ART 和 SUD 相关神经功能缺损中的作用。
- 批准号:
10561195 - 财政年份:2022
- 资助金额:
$ 65.88万 - 项目类别:
Spatiotemporal Staging of the HIV-1 Preintegration complex
HIV-1 预整合复合体的时空分期
- 批准号:
10625528 - 财政年份:2022
- 资助金额:
$ 65.88万 - 项目类别:
Role of GRIN2 in ART and SUD associated neurological deficits.
GRIN2 在 ART 和 SUD 相关神经功能缺损中的作用。
- 批准号:
10701055 - 财政年份:2022
- 资助金额:
$ 65.88万 - 项目类别:
Enhancing Virology Training of Underrepresented Minority Students through Summer Research
通过暑期研究加强对代表性不足的少数民族学生的病毒学培训
- 批准号:
10313298 - 财政年份:2021
- 资助金额:
$ 65.88万 - 项目类别:
Enhancing Virology Training of Underrepresented Minority Students through Summer Research
通过暑期研究加强对代表性不足的少数民族学生的病毒学培训
- 批准号:
10669049 - 财政年份:2021
- 资助金额:
$ 65.88万 - 项目类别:
Enhancing Virology Training of Underrepresented Minority Students through Summer Research
通过暑期研究加强对代表性不足的少数民族学生的病毒学培训
- 批准号:
10458092 - 财政年份:2021
- 资助金额:
$ 65.88万 - 项目类别:
Role of the Viral Capsid in HIV-1 Integration
病毒衣壳在 HIV-1 整合中的作用
- 批准号:
10436824 - 财政年份:2019
- 资助金额:
$ 65.88万 - 项目类别:
Role of the Viral Capsid in HIV-1 Integration
病毒衣壳在 HIV-1 整合中的作用
- 批准号:
9977928 - 财政年份:2019
- 资助金额:
$ 65.88万 - 项目类别:
Role of the Viral Capsid in HIV-1 Integration
病毒衣壳在 HIV-1 整合中的作用
- 批准号:
10199944 - 财政年份:2019
- 资助金额:
$ 65.88万 - 项目类别:
Cocaine downregulates anti-HIV microRNAs in CD4+ T cells
可卡因下调 CD4 T 细胞中的抗 HIV microRNA
- 批准号:
8329914 - 财政年份:2012
- 资助金额:
$ 65.88万 - 项目类别:
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