HUMAN PAPILLOMAVIRUS (HPV) INTERACTION WITH SARS-CoV-2: CAN FRUIT FLY OFFER INSIGHT INTO THE MECHANISM OF THESE INTERACTIONS AND THERAPEUTIC DEVELOPMENT TO ELIMINATE COINFECTED CELLS?

Abstract

High-risk human papillomaviruses (HR-HPVs) drive nearly all cervical cancers, and a significant number of vaginal, vulvar, penile, and oropharyngeal cancers through the persistent expression of HPV viral oncogenes E6 and E7. Although HPV vaccines are available, due to the long latency period, low vaccination rate, and the lack of molecularly targeted drugs for early treatment, the incidence of HPV-associated cancers continues to rise. Therefore, understanding the mechanisms of HPV-induced tumorigenesis is critical for developing new and effective strategies to prevent and treat the disease. Recently, synergistic interactions between HPV and SARS-CoV-2 have been reported, and it has been shown that cervical intraepithelial neoplasia and the epithelial cells of the oral mucosa harbor factors necessary for SARS-CoV-2 infection. However, no study to date has investigated the functional interaction between the two viruses and their impact on disease progression. Understanding these interactions is crucial for identifying actionable drug targets to eliminate coinfected cells. In this study, we investigated functional interaction between HPV and SARS-CoV-2 genes using transgenic Drosophila (the fruit fly) expressing viral genes. Using a Gal4-UAS binary expression system to direct gene expression in the desired tissue, we performed a functional genetic screen to identify SARS-CoV-2 genes whose expression modified HPVE6 oncogene-induced defects. We found that among all SARS-CoV-2 genes tested, only nsp3, nsp6, ORF6, and ORF3a functionally interacted with E6 oncoprotein. Further examination revealed that SARS-CoV-2 genes nsp3 and ORF3a induced apoptosis in both eye and wing epithelia, whereas ORF6 triggered apoptosis only in the wing epithelia, suggesting that ORF6 effect is tissue dependent. Despite these differences, all of them altered the oncogenic effect of E6 oncogene. Furthermore, we show that while E6 suppressed Wingless (Wg) expression ORF6 restored Wg signaling in this context. These findings demonstrates the first evidence of interaction between HPV oncogenes and SARS-CoV-2 genes in the same cells. This could have implications for understanding how viral co-exposures can impact disease progression or therapeutic responses in HPV-driven cancers.