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: 10477371
• 负责人: Rachel Adria Katzenellenbogen
• 金额: $ 16.09万
• 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/10477371
• 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; 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.

摘要 高危型人乳头瘤病毒（HR HPV）是宫颈癌的病原体， 80%的病例集中在低收入和中等收入国家（LMIC），进一步集中在非洲 像肯尼亚和乌干达。有针对HPV的预防性疫苗，但世界上只有不到2%的 目标人群收到了。这使数百万妇女面临患宫颈癌的风险。我们需要 了解HR HPV如何影响其宿主细胞，失调其环境，以及在高共- HR HPV和HIV感染与HIV协同作用，推动女性癌症的发展和进展。 宫颈癌发展的最大临床风险因素是持续性HR HPV感染。当 HR HPV感染宫颈，它改变了典型的细胞生长和分化的顺序激活 这两种途径都支持HR HPV感染和促进癌症发展。在艾滋病毒存在的情况下， HR HPV感染的宿主细胞的途径和功能被进一步破坏，导致更快的进展， 癌我们假设HR HPV感染表现为可预测的细胞基因表达变化， 在宫颈样本、活检组织和外周血中可检测到。对于HIV合并感染，我们假设 也可检测到增强的或独特的基因表达变化的另外的重叠子集。作为 总之，这些变化可以作为功能性生物标志物来前瞻性地识别癌前病变， 在她的艾滋病毒状况的背景下，对妇女未来患宫颈癌的风险进行分层。识别和验证这些 生物标志物是具体目标1的目标。 除了预测癌症风险的细胞生物标志物外，HR HPV的类型和变体也是一个重要的 预测与宫颈癌诊断相关的发病率和死亡率。目前，缺乏 HPV 16变异体遗传格局的基础数据，HPV 16是侵袭性淋巴瘤中最常见的HR HPV类型。 肯尼亚和乌干达的宫颈癌。我们假设特定的HPV 16变异增加了该区域的宫颈癌。 癌症风险;生成关于HPV 16变体的详细数据是具体目标2的目标。 我们的具体目标是：（1）确定宿主基因表达的差异， 在艾滋病毒+和艾滋病毒-女性中，宫颈发育不良和癌前病变的风险。我们将利用 同步收集宫颈拭子和组织、血液，并通过目视检查进行临床检查，以量化 宿主基因表达变化与病理学有关。(2)确定HIV+和HIV-中发现的HPV 16变异体 妇女我们将调查HPV 16变异并进行全基因组测序，以创建详细的图片 HPV 16基因多态性通过对HR HPV、其宿主细胞以及HR HPV在 我们将确定生物学和病毒学特征，指定一个HIV+或HIV-的妇女有感染HIV的风险。 宫颈癌的发展和进展。将在肯尼亚和乌干达进行这两个目标的研究， 在撒哈拉以南非洲扩大科学研究技术和未来的研究人员管道。