Immune drivers of oncogenic virus progression to cancer in people living with HIV

PROJECT SUMMARY/ABSTRACT The overarching goal of my research is to improve prevention, early detection, and outcomes of infection- related cancers, particularly among people living with HIV (PHIV) who experience an increased burden. Due to the immunosuppression and aberrant immune activation that accompanies lifelong HIV infection, PHIV have a higher prevalence of oncogenic infections (i.e. HPV) and those infections are more likely to persist and progress to cancer (i.e. cervical, anal, and oropharyngeal). My hypothesis is that systemic immune dysregulation is associated with an inability to control oncogenic infections and exacerbated in PHIV. Under this Catalyst Award, I plan to grow my research in the distinct direction of understanding the immune drivers of persistent oncogenic infections. To address this, I propose to start by utilizing a novel application of genome- wide DNA methylation. This recently published method can determine a person’s immune cell profile comprised of 12 immune cell subsets from the methylation array data, which can provide information on their overall immune function, which can then be investigated for its association with persistent oncogenic infections and progression to cancer. The first project I propose towards this goal will utilize specimens already available or currently being collected to investigate the immune drivers of oral HPV persistence, the pre-cursor to oropharyngeal cancer (OPC) by assessing the association between host immune cell profile and persistent oral hrHPV. Oropharyngeal cancer (OPC) caused by oral human papillomavirus (HPV) infection is increasing in incidence globally with a burden of disease disproportionately distributed among men and PHIV. A persistent oral high-risk HPV (hrHPV) infection has been identified as the obligate precursor to HPV-associated OPC (HPV-OPC) and can be utilized as a study endpoint. Therefore in this first study, methylation-based immune profile will be compared by oral HPV persistence status to understand the degree of immune function among study participants and its association with oral hrHPV persistence. I will then plan to repeat these methods for investigation at other HPV-related anatomic sites among the same participants and in other cohorts I serve as investigator. With a research background in basic science and molecular epidemiology I will be able to integrate multiple sources of data using a novel epigenetic tool not previously used to investigate persistent oncogenic infections among PHIV. My prior work has pursued overarching research interests within HPV- associated cancer or cancer among PHIV. The new direction of my research has a foundation in my prior work and expertise but represents movement in a new direction with a focus in immuno-oncology to gain insight into the immune drivers of persistent oncogenic infection that progresses to cancer among PHIV.