Multi-Omics Predictors of Oral HPV Outcomes among PLWH

PROJECT SUMMARY/ABSTRACT Advances in antiretroviral therapy (ART) have not reduced the disproportional incidence and prevalence of oral human papilloma virus (HPV) and oropharyngeal cancers in people living with HIV (PLWH), suggesting ART alone may not fully restore mucosal immunity. This may be because HIV alters the oral microbiome, affecting mucosal immunity, and biological aging, such as changes in DNA methylation and immune senescence, can worsen HIV-associated immunosuppression. Reshaping the microbiome or reprogramming DNA methylation patterns may be a safe way to identify, prevent, or treat HPV persistence; however, understanding how these factors interact to promote cancer is a crucial gap in our existing knowledge. Our objective is to investigate these two biological processes (oral microbiome, biological aging), combined with socioeconomic and behavioral factors (sexual practices, lifestyle factors) to determine the impact of the natural history of HPV infection in PLWH, and to construct a machine learning classifier using these factors that can predict HPV infection and persistence. Our overarching hypothesis is that dysbiosis of the oral microbiome and older methylation aging are risk factors for HPV-related complications and can dampen the mucosal immune response in PLWH. Therefore, this proposed longitudinal study plans to collect saliva at two time points (baseline and after six months) from 150 virologically suppressed PLWH (men and women, ≥21 years old) from Puerto Rico CoNCRA, a community-based organization specialized in the prevention and treatment of HIV. PLWH who attend PR CoNCRA constitute a unique high-risk group where the prevalence of both HIV and oral HPV infection is higher, allowing our team of experts in HIV, HPV, epidemiology, cancer biology, oral health and bioinformatics to establish these relationships with high efficiency. The specific aims of this proposal are: (1) to determine how HPV incident infection and persistence affects the oral microbiome and oxidative stress in saliva in PLWH, (ii) to characterize the oral methylome of PLWH with and without HPV and assess the impact of methylation aging in the natural history of HPV infection, and (iii) to construct a diagnostic and prognostic classifier based on biological data (microbiome and methylation) and socio-behavioral characteristics capable of discriminating HPV infection and persistence among PLWH. We will characterize the oral microbiota by 16S rDNA sequencing, HPV genotypes by PCR, DNA methylation by Illumina Infinium Methylation BeadChip arrays and oxidative stress by immuno spectrophotometry assays. Additionally, remaining saliva and voluntary blood collection will be used to create a biorepository for future research. This study leverages resources from the UPRCCC and CePCHE including (i) the UPRCCC Biobank for the biospecimen storage, (ii) the Biostatistics and Bioinformatics Core for assistance in the analyses and storage of the data generated, and (iii) the Outreach Core to help with participant recruitment and promotion of his project. This study will also provide data needed for R01 submission, and graduation of Dr. Josué Pérez-Santiago as a project leader of CePCHE.