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.

Grant Number: 5R01DE032242-04
NIH Institute/Center: NIH
Principal Investigator: Robert Burk