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

点击翻译按钮获取中文摘要

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.