Epigenetics of dysfunctional oral epithelium in people living with HIV and risk for HPV infection

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With the increase in life expectancy of people living with HIV (PLWH), principally due to the introduction of antiretroviral therapy (ART), it has become evident that these individuals differentially acquire a wide range of health problems, including oral health complications, which severely impact quality of life and incur substantial healthcare costs. We previously identified an altered proteomic profile of human oral keratinocytes isolated from PLWH patients, suggesting elevated cellular stress and reduced ability to provide robust innate immune protection. We also demonstrated that these epithelial cells display altered epigenetic markers, reduced proliferative capacity and respond weakly to microbial challenges. We now hypothesize that in PLWH, oral epithelial cell dysfunction predisposes towards susceptibility to secondary viral infections, such as HPV. We have assembled an interdisciplinary team of experts whose expertise encompasses HIV and HPV virology, oral and epithelial cell biology, epigenomics and bioinformatics. We propose to apply a novel non-invasive method of collecting oral mucosal cells from PLWH and conduct genomic and epigenomic analyses of the oral epithelium (Aim 1). Additionally, using a relevant HPV infection model, we wish to determine if such cells expanded from the oral mucosa of PLWH, which we have demonstrated exhibit an altered proteome, are more susceptible to HPV infection when compared to oral epithelial cells from healthy controls (Aim 2). These studies will be the first to establish the transcriptomic and epigenomic effects of HIV infection on primary epithelial cells, establish a new culture-based assay system so critical for future mechanistic and therapeutic studies, and enable direct comparisons between these in vivo and in vitro methods to robustly identify key molecular features that are central to the increased HPV susceptibility seen in PLWH. Successful completion of the goals of this R21 will enable targeted hypothesis-based genomic or epigenomic studies (i.e. shRNAs, CRISPR, or small molecules) to identify specific genes/pathways mediating the HPV susceptibility, and functionally test HPV infection levels. Validating the epigenetic basis of susceptibility to HPV infection in PLWH will eventually guide the discovery and application of novel epigenomic-based clinical interventions; all consistent with the goals of the NOSI NOT-DE-21-019 “Basic and translational oral health research related to HIV/AIDS.”