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
• 负责人: Corey Casper
• 金额: $ 142.33万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767057
• 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; Dysplasia; Enrollment; Event; Frequencies; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; HIV; HIV Infections; HPV-High Risk; Human Papillomavirus; Human papilloma virus infection; Immune; Immunity; Immunologics; Immunosuppressive Agents; 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; SLEB2 gene; 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; cohort; cost effective; cytotoxic; density; gene function; immunopathology; immunoregulation; improved; innovation; insight; integration site; member; neoplastic; new technology; novel; peripheral blood; predictive marker; 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（由适用提供）：归因于人乳头瘤病毒（HPV）感染的癌症是世界上最常见的HIV相关恶性肿瘤；在美国，撒哈拉以南非洲和肛门癌的特定宫颈癌。尚未完全理解导致这些增加几率的机制。与其他与其他HIV相关的恶性肿瘤相反，宫颈癌的事件与CD4+ T细胞计数Nadir的深度不完全相关，这表明除了不足的CD4+“帮助”易感HIV感染的HIV感染的个体以及其他HPV与HPV与HPV相关的癌症。我们的小组和其他人提出了一个重要的观察，即HIV整合到某些基因似乎可以调节宿主基因的表达，以促进感染T细胞的增殖和持久性。新兴数据表明，HIV整合会使幼稚的CD4+ T细胞分化为T调节细胞，从而为持续的HIV感染的免疫病理学提供了进一步的机械见解。优先观察结果与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整合到宿主基因中，调节T调节细胞是通过基于肿瘤的免疫组织化学的改变HIV感染的个体中宫颈癌发展的一部分。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合作合作，将HIV整合定义为与HPV感染的宫颈组织中与T调节细胞功能相关的基因。我们将注册HIV感染和未感染的乌干达妇女，具有阳性的宫颈癌筛查测试（用乙酸视觉检查），并鉴定患有高风险HPV感染的患者。在第一个目的中，我们将将HIV整合位点，T调节细胞的密度与HIV Proviruse的密度以及在已经发展为前癌/癌的女性的宫颈组织中的检查点分子的表达以及HIV感染的女性以及具有高风险HPV感染的赞助妇女。此外，将比较感染的HIV感染的HIV感染的妇女与宫颈肿瘤的蛋白质组途径和细胞毒性T细胞的蛋白质组途径，并与患有高危HPV的未感染的女性有可能清除其HPV。在第二个目标中，我们将评估渗透宫颈发育不良的Provirus的CD4+ T细胞克隆的宿主基因功能。具体而言，我们将使用外周血中检测到的克隆中的细胞来表征这些细胞克隆的T细胞标记。使用新技术，使用一种新型技术，将从单个HIV感染细胞的迷你文化中扩展从渗透宫颈发育不良的克隆中感染HIV的循环CD4+ T细胞，以全面表征HIV病毒和周围宿主基因组。最后，将评估通过将HIV LTR启动子插入发现在宫颈癌病例中被禁用的基因组部位中，概括幼稚CD4+ T细胞的转录组和表型变化的能力。这些数据将共同告知HIV是否以及如何在宿主基因中融合到与HPV相关癌症的风险增加，并指出新的干预措施以治疗持续的HPV感染。