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各地最常见的 HIV 相关恶性肿瘤；特别是撒哈拉以南非洲地区的宫颈癌和美国长期幸存者中的肛门癌。导致这些几率增加的机制尚不完全清楚。与其他 HIV 相关恶性肿瘤相比，宫颈癌的发病率并不完全与 CD4+ T 细胞计数最低点的深度相关，这表明除了 CD4+“帮助”不足之外，还有一种机制使 HIV 感染者容易患宫颈癌和其他 HPV 相关癌症。我们的小组和其他人做出了重要的观察，即 HIV 整合到某些基因中似乎可以调节宿主基因表达，以有利于受感染 T 细胞的增殖和持久性。新数据表明，HIV 整合可以使初始 CD4+ T 细胞分化为 T 调节细胞，从而为持续 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，得出了我们的总体假设：HIV 整合到调节 T 调节细胞的宿主基因中，通过改变基于肿瘤的免疫，是 HIV 感染者宫颈癌发展的组成部分。为了评估这一假设，我们将利用与乌干达癌症研究所的良好合作来确定 HIV 与 HPV 感染宫颈组织中 T 调节细胞功能相关基因的整合。我们将招募宫颈癌筛查试验（醋酸目视检查）呈阳性的 HIV 感染者和未感染者乌干达女性，并识别出高危 HPV 感染者进行研究。在第一个目标中，我们将比较已发展为癌前期/癌的女性与自发清除高危 HPV 感染的 HIV 感染女性的 HIV 整合位点、HIV 前病毒的 T 调节细胞密度以及检查点分子在宫颈组织中的表达。此外，还将比较进展为宫颈肿瘤的 HIV 感染女性与可能清除 HPV 的未感染高危 HPV 女性之间的 T 调节细胞和细胞毒性 T 细胞的蛋白质组通路。在第二个目标中，我们将评估具有浸润宫颈发育不良的原病毒的 CD4+ T 细胞克隆的宿主基因功能。具体来说，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 细胞标记。来自浸润宫颈不典型增生的克隆的 HIV 感染的循环 CD4+ 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 原病毒和周围宿主基因组。最后，将评估通过将 HIV LTR 启动子插入到在宫颈癌病例中发现被破坏的基因组位点来重现初始 CD4+ T 细胞转录组和表型变化的能力。这些数据将共同揭示 HIV 整合到宿主基因中是否以及如何增加 HPV 相关癌症的风险，并指出治疗持续性 HPV 感染的新干预措施。