Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
基本信息
- 批准号:10460575
- 负责人:
- 金额:$ 78.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAcquired Immunodeficiency SyndromeAddressAdherenceAgeAnatomyAutopsyBiological MarkersBloodBrainCCR5 geneCD4 Positive T LymphocytesCXCR4 geneCell physiologyCellsClinical TrialsCollectionControlled StudyCuesDNADataDevelopmentDisease ProgressionDisease remissionEnrollmentEquilibriumFingerprintGenetic FingerprintingsGoalsHIVHIV InfectionsIn VitroIndividualInfectionInflammationInterruptionInterventionKineticsLocationLongevityMacaca mulattaMediatingModelingNatureNeuraxisNeuropathogenesisPersonsPhagocytosisPrimatesRecording of previous eventsRegimenResearchResearch PersonnelResidual stateResistanceRestRoleSIVSpecimenT-Cell DepletionTimeTissuesVariantViralViral GenomeViral Load resultViral reservoirVirionVirusVirus LatencyVirus ReplicationWorkanimal resourceantiretroviral therapybrain tissueclinically relevantcostdesigndetection limitin vivoinsightmacrophagememory CD4 T lymphocytemultidisciplinarynovelnovel strategiesnovel therapeutic interventionpeerside effectsocial stigmasuccesssynergismviral DNAviral RNAviral rebound
项目摘要
Abstract
Despite its success at suppressing viral loads, antiretroviral therapy (ART) cannot eradicate HIV infection. The
main obstacle to curing HIV infection is the ability of the virus to persist under suppressive ART in reservoirs of
latently infected cells, which are established early after infection and supports rebound to pre-treatment levels
if ART is interrupted. Despite the extraordinary challenge of persistent virus reservoirs, a few cases have
recently proved that prolonged viral remission after analytical therapy interruption (ATI) is possible.
Unfortunately, the specific mechanisms regulating HIV rebound remain very poorly understood, thus critically
limiting the development of novel therapeutic strategies aimed at eradication or remission of HIV infection. In
this project, we have assembled a multidisciplinary team of investigators to address directly in vivo how the
size and relative distribution of the reservoir in CD4 T cells and macrophages govern (i) the anatomic
location of persistent viral reservoirs; (ii) the exent of residual inflammation and neuropathogenesis;
and (iii) the time and extent of viral rebound after ATI. Specifically, we propose to alter directly in vivo and
in a highly relevant model for HIV infection (i.e., the SIV infection of rhesus macaques; RMs) the overall size of
virus reservoirs and its distribution between CD4 T cells and macrophages. These goals will be achieved (i) by
using the well-established model of ART-treated, SIV-infected RMs; (ii) by using a SIV swarm that allows
tracking of multiple viral variants; and (iii) by performing in vivo Ab-mediated CD4 T cell depletion before SIV
infection and after SIV-infection during suppressive ART. We will determine how the planned in vivo depleting
interventions alter the distribution of viral reservoirs between CD4 T cells and macrophages; impact the
kinetics and extent of viral rebound following ATI; and influence the cellular nature and genetic fingerprinting of
the rebounding virus. Finally, we will investigate the mechanisms favoring SIV infection and persistence in
macrophages when CD4 T cells are depleted.
We believe that the complementary, comprehensive, highly synergistic, and rigourosly controlled studies that
we propose will provide unprecedented, novel insights into (i) understanding how the cellular nature of the viral
reservoir regulate residual inflammation and viral persistence on ART and viral rebound after ATI, and (2) the
direct role of macrophages in harboring replication competent virus during long-term ART and contributing to
viral rebound after ATI. Critical for our aims, the SIV/RM model allows for investigating the CD4 T cells versus
macrophages contribution to viral reservoir not only in blood, but also in a large number of tissues collected
longitudinally and at necropsy, including CSF and brain tissues. These achievements will inform efforts to
design novel therapeutic strategies aimed at achieving prolonged viral remission of HIV infection.
摘要
项目成果
期刊论文数量(0)
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{{ truncateString('JACOB D ESTES', 18)}}的其他基金
Selection and Evolution of HIV-1 reservoir cells in blood and tissues
血液和组织中 HIV-1 储存细胞的选择和进化
- 批准号:
10176754 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
- 批准号:
10673779 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Selection and Evolution of HIV-1 reservoir cells in blood and tissues
血液和组织中 HIV-1 储存细胞的选择和进化
- 批准号:
10465135 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
- 批准号:
10082887 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Selection and Evolution of HIV-1 reservoir cells in blood and tissues
血液和组织中 HIV-1 储存细胞的选择和进化
- 批准号:
10269039 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
- 批准号:
10251333 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Novel ISH Approaches to Quantify Replication Competent Reservoirs
量化复制能力储库的新 ISH 方法
- 批准号:
10413135 - 财政年份:2019
- 资助金额:
$ 78.67万 - 项目类别:
Novel ISH Approaches to Quantify Replication Competent Reservoirs
量化复制能力储库的新 ISH 方法
- 批准号:
10164715 - 财政年份:2019
- 资助金额:
$ 78.67万 - 项目类别:
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