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: 9982848
• 负责人: Corey Casper
• 金额: $ 136.55万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9982848
• 关键词: AIDS related cancer; Acetic Acids; Address; Affect; Africa South of the Sahara; African; Antibodies; Antiviral Agents; Antiviral Response; BACH2 gene; Biopsy; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Control; Carcinoma; Cell Count; Cell Proliferation; Cell physiology; Cells; Cervical; Cervical Cancer Screening; Cervical Intraepithelial Neoplasia; Cervical Squamous Cell Carcinoma; Cervical dysplasia; Cervix Neoplasms; Cervix Uteri; Characteristics; Clone Cells; Collaborations; Cytotoxic T-Lymphocytes; Data; Development; Diagnosis; Disease; Enrollment; Event; Frequencies; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; HIV; HIV Infections; HPV-High Risk; High grade dysplasia; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immune; Immunity; Immunologics; Incidence; Individual; Infiltration; Institutes; Intervention; Knowledge; Lead; Lesion; Long-Term Survivors; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Mediating; Modification; Morbidity - disease rate; Neoplasms; Oncogenes; Outcome; Pathogenesis; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Proliferating; Proteome; Proviruses; Regulatory T-Lymphocyte; Risk; Role; STAT5B gene; Secondary Prevention; Secondary to; Signal Transduction; Site; Structure; Susceptibility Gene; T-Lymphocyte; Testing; Therapeutic; Tissues; Transcript; Uganda; United States; Uterus; Visual; Woman; antiretroviral therapy; base; cancer cell; cervical biopsy; cohort; cost effective; cytotoxic; density; gene function; immunopathology; immunoregulation; improved; innovation; insight; integration site; member; neoplastic; new technology; novel; peripheral blood; predictive marker; programmed cell death protein 1; promoter; protein expression; public health relevance; transcriptome; tumor; tumor microenvironment

 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.

 描述（由申请人提供）：人乳头瘤病毒（HPV）感染引起的癌症是世界上最常见的HIV相关恶性肿瘤;特别是撒哈拉以南非洲的宫颈癌和美国长期存活者的肛门癌。导致这些几率增加的机制尚未完全了解。与其他HIV相关恶性肿瘤相比，宫颈癌的发病率与CD 4 + T细胞计数最低点的深度并不完全相关，这表明除了CD 4+“帮助”不足外，还有一种机制使HIV感染者易患宫颈癌和其他HPV相关癌症。我们的研究小组和其他研究人员进行了重要的观察，即HIV整合到某些基因中似乎可以调节宿主基因的表达，以促进受感染T细胞的增殖和持续存在。新出现的数据表明，HIV整合可以使幼稚CD 4 + T细胞分化为T调节细胞，为持续HIV感染的免疫病理学提供进一步的机制见解。上述观察结果与T调节细胞在宫颈癌中的公认作用相结合，导致我们的总体假设，即HIV整合到调节T调节细胞的宿主基因中是通过改变基于肿瘤的免疫力而在HIV感染个体中发展宫颈癌的组成部分。为了评估这一假设，我们将利用与乌干达癌症研究所建立的良好合作，以确定HIV整合到HPV感染的宫颈组织中与T调节细胞功能相关的基因中。我们将招募宫颈癌筛查试验（醋酸目视检查）阳性的艾滋病毒感染和未感染的乌干达妇女，并确定高危HPV感染者进行研究。在第一个目标中，我们将比较HIV整合位点、具有HIV前病毒的T调节细胞的密度以及已经进展到癌前/癌的妇女与具有自发清除高危HPV感染的HIV感染妇女的宫颈组织中检查点分子的表达。此外，调节性T细胞和细胞毒性T细胞的蛋白质组途径将在HIV感染的妇女与宫颈肿瘤进展之间进行比较-未感染的高危HPV妇女可能清除HPV。在第二个目标，我们将评估宿主基因功能的CD 4 + T细胞克隆与前病毒浸润宫颈异型增生。具体而言，我们将使用外周血中检测到的克隆细胞来表征这些细胞克隆的T细胞标志物。来自浸润宫颈异型增生的克隆的HIV感染的循环CD 4 + T细胞将使用新技术从单个HIV感染细胞的微型培养物中扩增，以全面表征HIV前病毒和周围宿主基因组。最后，将评估通过将HIV LTR启动子插入宫颈癌病例中被破坏的基因组位点来重现幼稚CD 4 + T细胞中转录组和表型变化的能力。这些数据将共同告知HIV整合到宿主基因中是否以及如何使HPV相关癌症的风险增加，并指出治疗持续性HPV感染的新干预措施。