Mechanisms of transcriptional regulation of ccr5 and host genetic control of HIV
ccr5转录调控机制与HIV宿主遗传控制
基本信息
- 批准号:9926037
- 负责人:
- 金额:$ 76.13万
- 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:2020-01-17 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAfricaAfricanAfrican AmericanAmericanAsian AmericansAuthorization documentationBioinformaticsBiological AssayCCR5 geneCD4 Positive T LymphocytesCRISPR/Cas technologyCell surfaceCis-Acting SequenceClinicClustered Regularly Interspaced Short Palindromic RepeatsCodeCollaborationsComplementary DNACoupledDNA sequencingDataDefectDisease remissionDistalDown-RegulationEnhancersEnterochromaffin CellsEthnic OriginEuropeanFamily memberFreezingGenesGeneticGenetic TranscriptionGenetic studyGenomicsGrantGuide RNAHIVHIV InfectionsHIV Long Terminal RepeatHLA-B AntigensHealthHispanic AmericansHomologous GeneHouseholdHumanIn VitroIndividualInheritance PatternsKineticsLaboratoriesLentivirus VectorLinkMaster&aposs DegreeMedicalMessenger RNAMethodsMolecularNaturePaperPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhenotypePopulationProductionProtein IsoformsProteinsPublishingRNARaceRecording of previous eventsReporterReproducibilityResistanceSamplingShipsSlaveT memory cellT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTechniquesTechnologyTestingTrainingTranscriptional RegulationTransfectionUgandaUniversitiesVariantVesicular stomatitis Indiana virusVirusVirus Replicationantiretroviral therapybasecausal variantchromosome conformation capturecohortexome sequencinggenetic pedigreegenome wide association studyimmune functionindexinginterestmacrophagenoveloverexpressionpandemic diseasereceptorrecruittranscription factortranscriptome sequencingvectorviral resistancevirology
项目摘要
Replication-competent human immunodeficiency virus (HIV) present in latently infected memory T cells
in HIV+ individuals is a major barrier to virus eradication, and in the history of the pandemic only two
individuals are thought to have been truly cured. There is, however, a small subset of HIV+ individuals who are
able to suppress viral replication to undetectable levels for years, in the absence of antiretroviral therapy.
These individuals, termed 'elite controllers' or ECs have been intensively studied, and genome-wide
association studies indicate that virologic control is due to coding variants in the HLA-B class I molecule, but
that can explain only ~20% of the effect. This suggests that other, perhaps non-immune based mechanisms,
are responsible for the EC phenotype. We were interested in linking the EC phenotype to genetic or
transcriptional changes, and by studying nearly 200 ECs (and viremic controllers or VCs) we were able to
demonstrate that a subset of them have CD4+ T cells that are relatively resistant to R5-tropic viruses in single
cycle infectivity assays. This in vitro phenotype, seen in ~20% of all EC/VCs, was highly reproducible,
depended upon the method of T cell activation, not observed in macrophages, and reversed by the introduction
of CCR5, the R5 co-receptor. This phenotype of in vitro R5 virus resistance inversely correlated with both
mRNA and protein levels of CCR5 and CCR2, the latter being the closest homolog to CCR5 and just 10 kb
upstream. The effect, however, extended for hundreds of kb surrounding ccr5/ccr2. Family members of Index
ECs with this phenotype had similar decreases in both ccr5 and ccr2 RNA levels, suggesting an autosomal
dominant inheritance pattern. ccr5 and ccr2 RNA half-lives were identical to those of non-resistant ECs,
suggesting that the effect was not post-transcriptional in nature, and ChIP data were consistent with a
transcriptional effect. Here we wish to further explore the mechanism(s) underpinning this phenotype. In the
first aim we will determine how both ccr5 and ccr2 are transcriptionally regulated in primary CD4+ T cells. We
will perform an unbiased CRISPR KO screen in primary T cells to identify genes which regulate ccr5/ccr2.
Chromosome conformation capture methods will be used to identify putative enhancers for the ccr5/ccr2 loci,
confirmed by functional studies, including use of advanced CRISPR/dCas9 techniques. We will also examine
the molecular basis of CD4 T cell resistance to replication-competent virus, since we have observed profound
inhibition of X4 virus in CD4+ T cells of these ECs. This will include KO of up-regulated restriction factors and
other genes, as seen by RNA-Seq. Finally, in an ongoing collaboration with Makerere University in Kampala,
Uganda we wish to extend these studies to East Africans, who are genetically distinct from our cohorts. CD4+
T cells from EC/VCs will be analyzed as described above to identify potentially novel mechanisms of host
genetic control. At the conclusion of these studies we hope to have a more complete understanding as to how
these EC/VCs are able to control viral replication and achieve functional cure while retaining immune function.
人类免疫缺陷病毒(HIV)存在于潜伏感染的记忆T细胞中
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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{{ truncateString('Richard Sutton', 18)}}的其他基金
Mechanisms of transcriptional regulation of ccr5 and host genetic control of HIV
ccr5转录调控机制与HIV宿主遗传控制
- 批准号:
10542351 - 财政年份:2020
- 资助金额:
$ 76.13万 - 项目类别:
Mechanisms of transcriptional regulation of ccr5 and host genetic control of HIV
ccr5转录调控机制与HIV宿主遗传控制
- 批准号:
10320936 - 财政年份:2020
- 资助金额:
$ 76.13万 - 项目类别:
Production of HIV vector supernatant using helper-dependent adenovirus
使用辅助依赖性腺病毒生产 HIV 载体上清液
- 批准号:
8340244 - 财政年份:2012
- 资助金额:
$ 76.13万 - 项目类别:
Production of HIV vector supernatant using helper-dependent adenovirus
使用辅助依赖性腺病毒生产 HIV 载体上清液
- 批准号:
8416938 - 财政年份:2012
- 资助金额:
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Probing blocks to infectious HIV release in mouse cells
探究小鼠细胞中感染性艾滋病毒释放的阻断
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7750034 - 财政年份:2008
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