Human papillomavirus (HPV) infection is the most common sexually transmitted disease and claims more than 270,000 women's lives from cervical cancer annually. Two protective HPV vaccines hold promise to substantially reduce HPV related cancers in the coming years. However, these vaccines offer no protection against pre-existing infections. In addition, the uptake of these vaccines is very low worldwide due to social and economic barriers. Therefore, HPV associated diseases and cancers will continue to be a public health problem until an effective therapeutic treatment is available. Although both males and females are exposed to HPV infections, more severe pathology is found in females, especially at ano-genital sites. The long term goal of this proposal is to gain a better understanding of the role of the menstrual cycle and hormonal contraceptives in papillomavirus infection and persistence. We propose to study papillomavirus infections at ano-genital sites using the newly discovered mouse papillomavirus (MmuPV1), which induces mild to high grade dysplasia at different ano-genital sites. We hypothesize that the changes in the ano-genital mucosal microenvironment during the menstrual cycle influence papillomavirus susceptibility and persistence in females. To test our primary hypotheses, we propose the following two specific aims.
Specific Aim 1 : To define the role of the estrous cycle in viral susceptibility at vaginal and anal mucosa. We hypothesize that different stages of the estrous cycle show differential susceptibility to viral infection at ano-genital sites. We will synchronize female mic at either the estrus or diestrus stage and infect them at both vaginal and anal sites. Viral production will be analyzed by Q-PCR from lavage samples. The resulting data will determine whether these stages of the estrous cycle are more or less susceptible to viral infection at vaginal and/or anal sites.
Specific Aim 2 : To determine the role of contraceptives on viral infection and persistence at vaginal and anal mucosa. We hypothesize that hormonal contraceptive usage increases viral infection and persistence. We will test two of the most commonly prescribed hormonally-based contraceptives and a non-hormonal contraceptive in this study. Lavage samples from virally infected vagina and anus will be collected for viral copy number quantification and histological analysis. Together, these studies promise to reveal new information about papillomavirus infections at female ano-genital sites. In particular, they should shed light on the role of the menstrual cycle and the influence of contraceptives on the disease. The proposed work will provide new evidence to guide individuals in making informed decisions about their contraceptive usage.

Public Health Relevance

We propose to use our newly established anogenital papillomavirus infection mouse model to determine the role of estrous cycle stage and contraceptive usage in viral susceptibility and persistence at vaginal and anal mucosa. These studies will shed light on the role of the menstrual cycle as well as contraceptives in papillomavirus-associated diseases and cancers.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Virology - B Study Section (VIRB)
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Hiltke, Thomas J
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Pennsylvania State University
Schools of Medicine
United States
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Cladel, Nancy M; Budgeon, Lynn R; Cooper, Timothy K et al. (2017) Mouse papillomavirus infections spread to cutaneous sites with progression to malignancy. J Gen Virol :
Christensen, Neil D; Budgeon, Lynn R; Cladel, Nancy M et al. (2017) Recent advances in preclinical model systems for papillomaviruses. Virus Res 231:108-118