1 The vaginal microbiome, papillomavirus infection, and cervical cancer: Established associations in search of model systems and mechanistic answers

High-risk human papillomavirus (HPV) infection is the causative factor for approximately 5% of all human cancers and the leading cause of cervical cancer. High-risk HPV-associated cervical cancer still claims more than 340,000 women’s lives globally each year despite the availability of prophylactic HPV vaccines. Currently, there is no medical treatment for HPV infections and associated lesions except invasive surgical procedures. For more than a decade, numerous studies have demonstrated a correlation between certain community state types (CSTs) of the vaginal microbiome and HPV-asso-ciated infection and cancer. This review aims to provide a general overview of the most recent studies on this topic, focusing primarily on clinical data linking a Lactobacillus-depleted vaginal microbiome (i.e., bacterial vaginosis and CST-IV) and HPV but also describing the limited mechanistic findings in the field. Finally, a novel mouse model addressing the causative effect of the vaginal microbiome on papillomavirus-associated disease progression and cancer development is proposed.