Anti-Retroviral Protease Inhibitors Regulate Human Papillomavirus 16 Infection of Primary Oral and Cervical Epithelium

SIMPLE SUMMARY: In 2016, globally, 36.7 million people were living with Human Immunodeficiency Virus (HIV), of which 53% had access to anti-retroviral therapy (ART) (UNAIDS 2017 Global HIV Statistics). The risk of Human Papillomavirus (HPV) associated oropharyngeal, cervical and anal cancers are higher among patients infected with HIV in the era of ART. Generally, HPV infections are self-limiting, however, persistent HPV infection is a major risk to carcinogenic progression. Long intervals between initial infection and cancer development imply cofactors are involved. Co-factors that increase infectivity, viral load, and persistence increase risk of cancer. We propose that the ART Protease Inhibitors (PI) class of drugs are novel co-factors that regulate HPV infection in HIV-infected patients. We developed a model system of organotypic epithelium to study impact of PI treatment on HPV16 infection. Our model could be used to study mechanisms of HPV infection in context of ART, and for developing drugs that minimize HPV infections. ABSTRACT: Epidemiology studies suggest that Human Immunodeficiency Virus (HIV)-infected patients on highly active anti-retroviral therapy (HAART) may be at increased risk of acquiring opportunistic Human Papillomavirus (HPV) infections and developing oral and cervical cancers. Effective HAART usage has improved survival but increased the risk for HPV-associated cancers. In this manuscript, we report that Protease Inhibitors (PI) treatment of three-dimensional tissues derived from primary human gingiva and cervical epithelial cells compromised cell-cell junctions within stratified epithelium and enhanced paracellular permeability of HPV16 to the basal layer for infection, culminating in de novo biosynthesis of progeny HPV16 as determined using 5-Bromo-2′-deoxyuridine (BrdU) labeling of newly synthesized genomes. We propose that HAART/PI represent a novel class of co-factors that modulate HPV infection of the target epithelium. Our in vitro tissue culture model is an important tool to study the mechanistic role of anti-retroviral drugs in promoting HPV infections in HAART-naïve primary epithelium. Changes in subsequent viral load could promote new infections, create HPV reservoirs that increase virus persistence, and increase the risk of oral and cervical cancer development in HIV-positive patients undergoing long-term HAART treatment.