Project 3-- Determining biological and viral factors associated with clinical progression of cervical dysplasia in HIV-infected women

项目 3——确定与 HIV 感染女性宫颈发育不良临床进展相关的生物和病毒因素

• 批准号: 10256044
• 负责人: Rachel Adria Katzenellenbogen
• 金额: $ 16.23万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10256044
• 关键词: AIDS/HIV problem; Affect; Africa; Africa South of the Sahara; African; Antigen Presentation; Biological; Biological Markers; Biopsy; Blood; CXCL1 gene; Cells; Cervical; Cervical dysplasia; Cervix Uteri; Clinical; Collection; Country; DNA Tumor Viruses; Data; Development; Diagnosis; Differentiation and Growth; Disease; Dysplasia; Environment; Epidemiology; Extracellular Matrix; Fingerprint; Fostering; Foundations; Future; Gene Expression; Genetic; Genetic Polymorphism; Genetic Variation; Goals; HIV; HIV Infections; HIV Seropositivity; HPV-High Risk; Healthcare; High Prevalence; High-Risk Cancer; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune response; Immunologic Adjuvants; Immunologic Surveillance; Immunomodulators; Infection; Innate Immune System; Investigation; Kenya; Knowledge; Lesion; Life Cycle Stages; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Mediating; Modification; Morbidity - disease rate; Natural Immunity; Oncogenes; Pathology; Pathway interactions; Prevalence; Prevention; Preventive vaccine; Proteins; RNA; Research Personnel; Research Technics; Retroviridae; Risk; Risk Factors; SLPI gene; Sampling; Signal Transduction; Swab; TERT gene; Target Populations; TimeLine; Tissues; Uganda; Variant; Viral; Viral Oncogene; Visual; Woman; Work; antiretroviral therapy; base; cancer diagnosis; cancer risk; cell growth; cellular targeting; clinical examination; clinical risk; co-infection; epidemiology study; experimental study; genetic risk factor; genome sequencing; high risk; improved; insight; low and middle-income countries; mortality; peripheral blood; predictive marker; premalignant; prospective; risk stratification; screening; skills; specific biomarkers; synergism; tumor microenvironment; tumor progression; virology; virus genetics; virus host interaction; whole genome

Abstract High-risk human papillomaviruses (HR HPVs) are the causative agent for cervical cancer, with more than 80% of cases clustered in low and middle income countries (LMIC), and a further concentration in African countries like Kenya and Uganda. There are preventive vaccines against HPV, but less than 2% of the world’s target population has received them. This leaves millions of women at risk for cervical cancer. We need to understand how HR HPV affects its host cell, dysregulates its environment, and, in regions with high rates of co- infection of HR HPV and HIV, synergizes with HIV to drive cancer development and progression in women. The greatest clinical risk factor for cervical cancer development is a persistent HR HPV infection. When HR HPV infects the cervix, it changes the typical, sequential activation of cellular growth and differentiation pathways both to support the HR HPV infection and to foster cancer development. In the presence of HIV, the pathways and functions of HR HPV infected host cells are further disrupted, leading a more rapid progression to cancer. We hypothesize that HR HPV infections manifest in predictable cellular gene expression changes that are detectable in cervical samples, biopsy tissues, and peripheral blood. With HIV co-infection, we hypothesize an additional, overlapping subset of augmented or unique gene expression changes are also detectable. As a collective, these changes can serve as functional biomarkers to prospectively identify precancerous lesions and, in the context of her HIV status, to stratify a woman’s future cervical cancer risk. Identifying and validating these biomarkers is the goal of Specific Aim 1. In addition to cellular biomarkers that predict cancer risk, the type and variant of HR HPVs is an important predictor of morbidity and mortality associated with a cervical cancer diagnosis. Currently, there is a lack of foundational data on the genetic landscape of variants of HPV 16, the most common HR HPV type in invasive cervical cancers in Kenya and Uganda. We hypothesize that specific HPV 16 variants add to this region’s cervical cancer risk; generating detailed data on HPV 16 variants is the goal of Specific Aim 2. Our specific aims are: (1) Determine differences in host gene expression that prospectively discriminate among HIV+ and HIV- women the risk for cervical dysplasia and precancerous lesions. We will leverage the synchronous collection of cervical swabs and tissue, blood, and a clinical exam by visual inspection to quantify host gene expression changes linked to pathology. (2) Determine the HPV 16 variants found in HIV+ and HIV- women. We will investigate HPV 16 variants and conduct whole genome sequencing to create a detailed picture of HPV 16 genetic polymorphisms. Through investigations of HR HPV, its host cells, and HR HPV in the context of HIV, we will determine the biologic and virologic signatures designating a HIV+ or HIV- woman at risk for cervical cancer development and progression. Studies for both aims will be performed in Kenya and Uganda, expanding scientific research techniques and future pipelines of investigators in Sub-Saharan Africa.

抽象的 高风险人乳头瘤病毒（HR HPV）是宫颈癌的病因，多于 80％的案件聚集在低矮的中等收入国家（LMIC），非洲进一步集中 肯尼亚和乌干达等国家都有预防疫苗 目标人群已经使数百万的妇女患有宫颈癌 了解HR HPV如何影响其宿主细胞，非环境失调是环境，并且在共同率高的地区 HR HPV和HIV的感染，具有HIVE协同作用，以推动女性的癌症发展和进步。 宫颈癌发展的最大临床风险因素是持续的HR HPV感染 HR HPV感染子宫颈，它改变了细胞生长和分化的典型，顺序激活 支持HR HPV感染的途径和在HIV存在下促进癌症的途径。 HR HPV感染的宿主细胞的途径和功能进一步破坏，导致程序更快 我们假设HR HPV感染在可预测的细胞基因表达中表现 在宫颈样品，活检组织和周围血液中可检测到。 增强或唯一表达式变化的另一个重叠子集也可以检测到。 集体，这些变化可以用作实用生物标志物，以识别识别癌前病变和 在她的艾滋病毒状况的背景下，以分层女性的未来宫颈癌风险。 生物标志物是特定目标1的目标。 除了预测癌症风险的细胞生物标志物外，HR HPV的类型和变异是重要的 预测与宫颈癌诊断相关的病态和死亡率。 HPV 16变体的遗传格局的基础数据，这是最常见的HR HPV类型在侵入性中 肯尼亚和乌干达的宫颈癌。 癌症风险；在HPV 16上产生详细的数据是特定目标2的目标。 我们的具体目的是：（1）确定前瞻性歧视的宿主基因表达的差异 在艾滋病毒+和艾滋病毒中，我们将利用宫颈发育不良的风险。 通过视觉检查的宫颈拭子和组织，血液和临床检查的同步收集以量化 宿主基因表达变化与病理相关。 女性。 HPV 16遗传多态性。 在艾滋病毒中，我们将确定指定艾滋病毒+或艾滋病毒的生物学和病毒学特征 宫颈癌的发展和进展。 扩大撒哈拉以南非洲研究人员的科学研究技术和未来的管道。