The role of antiretroviral therapy in susceptibility to oral human papillomavirus (HPV) infection

ABSTRACT People living with human immunodeficiency virus (HIV) infection (PLWH) remain at increased risk of developing head and neck squamous cell cancer (HNSCC) due to oncogenic human papillomavirus (HPV) infection, despite adequate management of HIV with effective antiretroviral therapy (ART). Clinical observations have indicated increased risk of oral HPV infection and pathology in PLWH after they begin taking ART and concurrent with a significant drop in HIV viral burden. Prior in vitro studies using 3D experimental tissue models that mimic stratified squamous epithelium have suggested that exposure of the tissue to ART agents disrupts the structural integrity of the tissue and enhances susceptibility to HPV infection. These findings have not been corroborated in clinical studies using relevant oral mucosal samples from PLWH. We hypothesize that ART damages the integrity of the oral mucosa and enhances acquisition of HPV infection in vivo. Further, we posit that individuals that are taking ART for pre-exposure prophylaxis (PrEP) to prevent HIV infection will exhibit tissue damage and HPV susceptibility similar to that of PLWH who are taking ART to manage their HIV infection. Three specific aims are proposed to investigate these hypotheses: 1) to compare the prevalence and incidence of oral HPV infection in PLWH taking ART and people taking ART for PrEP to risk-matched HIV seronegative, ART-naïve controls; 2) to examine the architecture of oral mucosal tissue in subjects taking ART/PrEP for evidence of damage to the integrity of the mucosal barrier; and 3) to determine the effect of taking ART/PrEP on tissue susceptibility to HPV infection by experimental challenge of patient oral biopsy-derived 3D tissues with HPV16 in vitro. These studies will, for the first time, discern the role of ART apart from HIV infection on oral mucosa integrity and susceptibility to oral HPV infection. This is significant because understanding the interplay between HIV, ART and HPV will reveal new opportunities to prevent HNSCC that take into consideration the effects of ART on patient risk.