A co-infection model for papillomavirus associated infections and cancers

Project: Research project

Project Details


Abstract HPV infections are the most common sexually transmitted diseases and the primary cause of cervical cancer. Cervical cancer remains to be the fourth most common female malignancy and the second most common female cancer in women aged 15 to 44 years and is estimated to cause 91% of HPV-related cancer deaths. Every year approximately 5.5 million new HPV infections are reported in the U.S; Although 90% of infections can be cleared within two years, about 10% persistent HPV infections will ultimately progress to invasive cancers. The current prophylactic HPV vaccines (Gardasil and Cervarix) cannot clear established infections, which could take up to 25 years to progress to malignancy. Clinical management of HPV-related cancers is challenging because the robust early diagnostics and curative treatments are yet to be developed. HPV persistence is one key factor for cervical cancer. Accumulated evidence has demonstrated that women with high levels of bacterial vaginosis (BV)-associated anaerobic organisms are at increased risk of HPV persistence. However, the cause/effect of BV in cervical cancer remains elusive. Surprisingly little is known about the molecular processes underpinning the relationship between BV-associated bacteria and HPV because co-infection model systems have not been established. The interdisciplinary team of Dr. Gilbert for vaginal microbiome and Dr. Hu for papillomavirus will be most suitable to develop a co-infection model to study the dynamic roles of vaginal bacteria and papillomavirus persistence during cervical cancer development. Our overarching hypotheses guiding this proposal are that BV bacteria promote HPV persistence and tumor progression, and sex hormone contraceptives promote HPV persistence and cancer by disrupting the vaginal microbiome. More specifically, we will test these hypotheses in two specific aims of the current proposal: 1) BV bacteria promote HPV persistence and cancers by degrading the vaginal mucus barrier, disturbing the vaginal epithelium and/or by modulating host inflammatory responses to HPV infections (Aim 1). 2) Sex hormonal contraceptives promote HPV persistence and cancer in the genital tract by disrupting the vaginal microbiome (Aim 2). The rationales for these aims are based on previous published studies and current needs. Two common contraceptives depo medroxy-progesterone acetate (DMPA) and 17 beta-estradiol may impair colonization of lactobacilli and possibly compromise the vaginal barrier to viral infections leading to HPV persistence and cancer. We will develop a new co-infection mouse model system based on the expertise of two teams in two novel mouse models necessary to directly examine the basic premise of our hypotheses in two specific Aims. These studies will provide a starting place for more detailed microbiological and biochemical examinations of the mechanisms driving the BV-HPV association in cervical cancer. Findings of the current proposed study will have significant implications not only in providing novel insight to both the vaginal microbiome and papillomavirus fields but also in identifying interventions for future translational studies.
Effective start/end date4/1/233/31/24


  • National Cancer Institute: $248,781.00


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