Clearance in asymptomatic genital HPV infections in young adult women is shaped by host immune response

Persistent infection with high-risk human papillomavirus (HPV) genotypes has been identified as a necessary etiological factor in cervical cancer, with HPV16 alone accounting for approximately 50-60% of these cases. Fortunately, the vast majority of genital HPV infections clear spontaneously within two years and without causing any symptoms. The mechanisms leading to this clearance, or more precisely absence of HPV detection, remain unclear. Yet, understanding the immunology of HPV clearance could help develop new biomarkers or therapies. Building on a longitudinal study of women with genital HPV infections, we analysed 100 samples using quantitative bulk RNA sequencing (RNA-seq) to identify potential host transcriptomic signatures associated with infection clearance in asymptomatic young women. Using Gene Set Enrichment Analysis (GSEA) to anaylse significantly enriched pathways across infection outcome categories, we found that HPV-positive infections were characterised by downregulation in both antiviral innate and adaptive immune responses. Additionally, amongst the HPV-positive infections, HPV16-positive infections were associated with downregulation of pathways related to the viral life cycle regulation. Furthermore, non-clearing infections were differentiated by adaptive immune response activation, and persistent infections were marked by downregulation of pathways related to tumor necrosis factor (TNF) production and regulation. This work represents one of the first transcriptomics analyses tackling asymptomatic HPV clearance. It suggests that adaptive immunity is the most prominent factor involved in HPV infection clearance and could be potentially used to further address future diagnostic and therapy-related challenges for HPV screening and prevention.