Impact of HIV, oral microbiome and mycobiome on oral HPV persistence

ABSTRACT Oral human papillomavirus (HPV) infections and HPV-associated papillomas and cancers continue to rise, especially in people living with HIV (PLWH). Specifically, rates of HPV-associated oral and oropharyngeal cancer are increasing at an alarming rate. Using large population-based longitudinal studies, our work indicated an increased risk of oral lesions and head and neck cancers with not only HPV16, but unexpectedly cutaneous beta and gamma HPVs as well. Studying risk factors, we identified an interaction between smoking and HIV serostatus with increased prevalence of oral high-risk alpha and beta-HPV detection. In addition to oral HPV, HIV affects the composition of the oral microbiome, which has also been associated with increased susceptibility to oral HPV infection, persistence, and progression to HPV-driven cancer. Taken together, these findings indicate a continuing public health concern of HPV-related oral diseases for PLWH. The proposed study will leverage repeat oral saliva samples collected from N=2046 male and female PLWH, and N=1334 HIV[-] individuals enrolled in the MACS-WIHS Combined Cohort Study (MWCSS). Specifically, we will investigate the associations between the oral microbiome and mycobiome and risk of acquisition and persistence of high-risk alpha, beta, and gamma oral HPV. The scientific premise of the study is that alterations in the oral microbiome / mycobiome resulting from HIV and smoking influence oral HPV natural history. We will use novel sequencing methods developed by our team, including next generation sequencing and metagenomics, to profile the HPV virome (alpha, beta, and gamma HPV), oral bacterial (16S rRNA) and fungal communities (using a recently developed ITS1 assay with increased sensitivity for Candida developed in the Burk lab), functional gene capacity (determined from shotgun metagenomic sequencing), and cytokine profiles (derived from oral saliva protein analyses). Differences in the oral microbiome / mycobiome between PLWH and HIV[-] individuals will be assessed, as well as markers of HIV disease and smoking, with respect to oral HPV persistence. Taking advantage of serial samples collected in MWCCS participants, we will characterize oral microbiome / mycobiome changes over time in response to CD4 count and HIV RNA level, smoking, and the oral microbiome / mycobiome to address the following specific aims: 1) Determine the combined effects of HIV and smoking on risk of oral HPV persistence; 2) Study the associations between the oral microbiome / mycobiome and risk of oral HPV persistence; 3) Characterize the microbial function and oral inflammation/immune pathways associated with risk of oral HPV persistence. We hypothesize that the oral microbiome and mycobiome influenced by HIV and smoking exhibit significantly higher proportions of virulence factors, which in turn dysregulate the oral barrier immunity and integrity, facilitating persistence of oral high-risk HPV types associated with increased risks for oral and oropharyngeal cancer.