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
• 负责人: Corey Casper
• 金额: $ 69.29万
• 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/9129244
• 关键词: Acetic Acids; Address; Affect; Africa South of the Sahara; African; Anti-Retroviral Agents; 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; 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; Proliferating; Proteome; Proviruses; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Risk; Role; STAT5B gene; Secondary Prevention; Signal Transduction; Site; Sorting - Cell Movement; Structure; Susceptibility Gene; T-Lymphocyte; Testing; Therapeutic; Tissues; Transcript; Uganda; United States; Visual; Woman; base; cancer cell; cohort; cost effective; cytotoxic; density; gene function; high risk; immunopathology; immunoregulation; improved; in vivo; 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.