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: 10084055
• 负责人: Rachel Adria Katzenellenbogen
• 金额: $ 16.93万
• 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/10084055
• 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 system; 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; response; 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 高危人乳头瘤病毒 (HR HPV) 是宫颈癌的病原体，超过 80%的病例集中在低收入和中等收入国家（LMIC），并且进一步集中在非洲 肯尼亚和乌干达等国家。有针对 HPV 的预防性疫苗，但全世界只有不到 2% 目标人群已收到。这使得数百万女性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、使其环境失调，以及在感染率高的地区 HR HPV 和 HIV 感染与 HIV 协同作用，推动女性癌症的发生和进展。 宫颈癌发展的最大临床危险因素是持续的 HR HPV 感染。什么时候 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 途径既支持 HR HPV 感染，又促进癌症发展。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，导致疾病进展更快 癌症。我们假设 HR HPV 感染表现为可预测的细胞基因表达变化， 可在宫颈样本、活检组织和外周血中检测到。对于 HIV 合并感染，我们假设 还可以检测到增强的或独特的基因表达变化的附加重叠子集。作为一个 总的来说，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， 根据她的艾滋病毒状况，对女性未来患宫颈癌的风险进行分层。识别并验证这些 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 的类型和变异也是一个重要的因素。 与宫颈癌诊断相关的发病率和死亡率的预测因子。目前，国内还缺乏 关于 HPV 16 变体遗传图谱的基础数据，HPV 16 是侵袭性中最常见的 HR HPV 类型 肯尼亚和乌干达的宫颈癌。我们假设特定的 HPV 16 变体会增加该区域的宫颈癌风险。 癌症风险；生成 HPV 16 变体的详细数据是特定目标 2 的目标。 我们的具体目标是：（1）确定宿主基因表达的差异，从而进行前瞻性区分 HIV+和HIV-女性患宫颈发育不良和癌前病变的风险。我们将利用 同步采集宫颈拭子和组织、血液，并通过目视检查进行量化临床检查 宿主基因表达变化与病理相关。 (2) 确定 HIV+ 和 HIV- 中发现的 HPV 16 变异体 女性。我们将研究 HPV 16 变体并进行全基因组测序以创建详细图片 HPV 16 基因多态性。通过对 HR HPV、其宿主细胞以及背景下的 HR HPV 的研究 的艾滋病毒，我们将确定生物和病毒学特征，指定艾滋病毒+或艾滋病毒-女性有感染风险 宫颈癌的发生和进展。这两个目标的研究将在肯尼亚和乌干达进行， 扩大撒哈拉以南非洲的科学研究技术和未来的研究人员渠道。