HIV integration-mediated modulation of immune regulation in HPV-associated cancers
HIV 整合介导的 HPV 相关癌症免疫调节调节
基本信息
- 批准号:9982848
- 负责人:
- 金额:$ 136.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS related cancerAcetic AcidsAddressAffectAfrica South of the SaharaAfricanAntibodiesAntiviral AgentsAntiviral ResponseBACH2 geneBiopsyCD4 Positive T LymphocytesCD8B1 geneCancer ControlCarcinomaCell CountCell ProliferationCell physiologyCellsCervicalCervical Cancer ScreeningCervical Intraepithelial NeoplasiaCervical Squamous Cell CarcinomaCervical dysplasiaCervix NeoplasmsCervix UteriCharacteristicsClone CellsCollaborationsCytotoxic T-LymphocytesDataDevelopmentDiagnosisDiseaseEnrollmentEventFrequenciesGene ExpressionGenesGenetic TranscriptionGenomeGenomicsHIVHIV InfectionsHPV-High RiskHigh grade dysplasiaHuman Papilloma Virus-Related Malignant NeoplasmHuman PapillomavirusHuman papilloma virus infectionImmuneImmunityImmunologicsIncidenceIndividualInfiltrationInstitutesInterventionKnowledgeLeadLesionLong-Term SurvivorsMalignant NeoplasmsMalignant neoplasm of anusMalignant neoplasm of cervix uteriMediatingModificationMorbidity - disease rateNeoplasmsOncogenesOutcomePathogenesisPathway interactionsPatternPeripheral Blood Mononuclear CellPersonsPhenotypeProliferatingProteomeProvirusesRegulatory T-LymphocyteRiskRoleSTAT5B geneSecondary PreventionSecondary toSignal TransductionSiteStructureSusceptibility GeneT-LymphocyteTestingTherapeuticTissuesTranscriptUgandaUnited StatesUterusVisualWomanantiretroviral therapybasecancer cellcervical biopsycohortcost effectivecytotoxicdensitygene functionimmunopathologyimmunoregulationimprovedinnovationinsightintegration sitememberneoplasticnew technologynovelperipheral bloodpredictive markerprogrammed cell death protein 1promoterprotein expressionpublic health relevancetranscriptometumortumor microenvironment
项目摘要
DESCRIPTION (provided by applicant): Cancers attributable to human papillomavirus (HPV) infections are the most common HIV-associated malignancies around the world; specifically cervical cancer in sub-Saharan Africa and anal cancer among long- term survivors in the United States. The mechanisms responsible for these increased odds are not completely understood. In contrast to other HIV-associated malignancies, the incidence of cervical cancer is not entirely related to the depth of CD4+ T-cell count nadir, suggesting that a mechanism in addition to inadequate CD4+ "help" predisposes HIV-infected individuals to cervical and other HPV-associated cancers. Our group and others made the important observation that HIV integration into certain genes appears to modulate host gene expression to favor proliferation and persistence of infected T-cells. Emerging data show that HIV integration can skew the differentiation of naïve CD4+ T-cells into T regulatory cells, providing further mechanistic insights to the immunopathology of persistent HIV infection. The aforementioned observations combined with the recognized role of T regulatory cells in cervical cancer led to our overarching hypothesis that HIV integration into host genes that modulate T regulatory cells are integral to the development of cervical cancer in HIV- infected individuals through alterations of tumor-based immunity. To evaluate this hypothesis, we will utilize a well established collaboration with the Uganda Cancer Institute to define HIV integration into genes associated with T regulatory cell function in HPV-infected cervical tissues. We will enroll HIV-infected and -uninfected Ugandan women with a positive cervical cancer screening test (visual inspection with acetic acid), and identify those with high-risk HPV infections for study. In the first Aim, we will compar HIV integration sites, density of T regulatory cells with HIV proviruses and expression of checkpoint molecules in the cervical tissue of women who have progressed to pre-cancer/carcinoma with HIV-infected women with spontaneous clearance of high- risk HPV infections. Furthermore, the proteome pathways of T regulatory cells and cytotoxic T cells will be compared between HIV-infected women with progression to cervical neoplasia with -uninfected women with high-risk HPV who are likely to clear their HPV. In the second Aim, we will evaluate host gene function of CD4+ T-cells clones with proviruses infiltrating the cervical dysplasia. Specifically, we will characterize the T-cell markers of these cell clones using cells from the clone detected in the peripheral blood. HIV-infected circulating CD4+ T-cells from the clones infiltrating the cervical dysplasia will be expanded from in mini-cultures of single HIV infected cells using a novel technology to comprehensively characterize the HIV provirus and surrounding host genome. Finally, the ability to recapitulate transcriptome and phenotypic changes in naïve CD4+ T-cells by insertion of the HIV LTR promoter into genomic sites found to be disrupted in cervical cancer cases will be evaluated. Together these data will inform whether and how HIV integration into host genes predisposes to an increased risk of HPV-associated cancers, and point to novel interventions to treat persistent HPV infections.
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)
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Corey Casper其他文献
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{{ truncateString('Corey Casper', 18)}}的其他基金
HIV integration-mediated modulation of immune regulation in HPV-associated cancers
HIV 整合介导的 HPV 相关癌症免疫调节调节
- 批准号:
9340125 - 财政年份:2016
- 资助金额:
$ 136.55万 - 项目类别:
HIV integration-mediated modulation of immune regulation in HPV-associated cancers
HIV 整合介导的 HPV 相关癌症免疫调节调节
- 批准号:
9129244 - 财政年份:2016
- 资助金额:
$ 136.55万 - 项目类别:
HIV integration-mediated modulation of immune regulation in HPV-associated cancers
HIV 整合介导的 HPV 相关癌症免疫调节调节
- 批准号:
9767057 - 财政年份:2016
- 资助金额:
$ 136.55万 - 项目类别:
Expanding independent research capacity in HIV-associated malignancies in Uganda
扩大乌干达艾滋病毒相关恶性肿瘤的独立研究能力
- 批准号:
8708481 - 财政年份:2014
- 资助金额:
$ 136.55万 - 项目类别:
Biologic Determinants of the Natural History of AIDS-Defining Cancers in Uganda
乌干达艾滋病定义癌症自然史的生物决定因素
- 批准号:
8929189 - 财政年份:2014
- 资助金额:
$ 136.55万 - 项目类别:
Biologic Determinants of the Natural History of AIDS-Defining Cancers in Uganda
乌干达艾滋病定义癌症自然史的生物决定因素
- 批准号:
8793997 - 财政年份:2014
- 资助金额:
$ 136.55万 - 项目类别:
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