Worldwide levels of cancers resulting from infection by human papillomaviruses (HPV) exceed 550,000 cases, 500,000 of these are cervical cancers. Current vaccine efforts aimed at preventing the initial infection target the onset of cervical cancer may reduce cervical cancer by 70%. However, because the vaccine covers infection by 2 of the more than 13 oncogenic HPV types, and because administration of the vaccine is cost- prohibited in developing countries where incidence of HPV cancer is highest, the success may be much less. Because HPV is a sexually transmitted disease, the prospect of reducing the burden of cancer and HPV disease by preventing the ability of the virus to establish infection is quite appealing and potentially achievable through vaccination. We postulate that HPVs utilize similar if not identical routes of entry, and defining common steps in infection will lead to a broad acting cost-effective antiviral. Our long-term goal is to identify host-pathogen interactions that can serve as targets for prevention of HPV infection regardless of type, species, and oncogenic potential. During FY2010, our laboratory's progressed successfully by demonstrating that heparan sulfate, a6 integrin, and focal adhesion kinase (FAK) play a role in the initial attachment and entry of HPV 16 in the human keratinocyte cell line HaCaT. These recent findings are described in our latest manuscript and recent in vivo data from Dr. Schiller's laboratory (NCI/NIH) using a murine cervico-vaginal model, supports our finding that heparan sulfate is necessary for initial binding events. Taken together with previous published data we hypothesize that after the initial capture of HPV by heparan sulfate containing molecules either in the extracellular matrix or at the plasma membrane, entry into cells is mediated by an endocytosis complex and FAK. The objective of this application is to identify this plasma membrane endocytosis complex and define the signal transduction events necessary for viral internalization and proper trafficking. We determined that blocking the initial activation of FAK was able to decrease infection. Because papillomaviruses may use a common infectious route, this latter finding suggests that defining the initial events leading to viral entry and intracellular trafficking may lead to novel antiviral approaches that may prove to be broad acting across PV genotypes. Our findings may also lead to a cost-effective antiviral that will enhance the global strategy aimed at reducing HPV infections worldwide.

Public Health Relevance

The proposed work is relevant to public health because identifying the mechanism by which human papillomavirus (HPV) bind and enter cells is critical in our development of continued strategies at preventing HPV infection. HPV is a DNA virus that is responsible for the development of human cancers including cervical, anal, and certain types of oropharyngeal tumors and of the majority of genital warts. HPV is considered the most common sexually transmitted disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA153096-01A1
Application #
8194786
Study Section
Special Emphasis Panel (ZRG1-OBT-A (50))
Program Officer
Wali, Anil
Project Start
2011-09-05
Project End
2013-08-31
Budget Start
2011-09-05
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$202,341
Indirect Cost
Name
Fordham University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071011019
City
Bronx
State
NY
Country
United States
Zip Code
10458
Aksoy, Pinar; Gottschalk, Elinor Y; Meneses, Patricio I (2017) HPV entry into cells. Mutat Res Rev Mutat Res 772:13-22
An, Xinwei; Hao, Yuhan; Meneses, Patricio I (2017) Host cell transcriptome modification upon exogenous HPV16 L2 protein expression. Oncotarget 8:90730-90747
Gottschalk, Elinor Y; Meneses, Patricio I (2015) A Dual Role for the Nonreceptor Tyrosine Kinase Pyk2 during the Intracellular Trafficking of Human Papillomavirus 16. J Virol 89:9103-14
Kumar, Annandita; Jacob, Taylor; Abban, Cynthia Y et al. (2014) Intermediate heparan sulfate binding during HPV-16 infection in HaCaTs. Am J Ther 21:331-42
Aksoy, P?nar; Abban, Cynthia Y; Kiyashka, Elizabeth et al. (2014) HPV16 infection of HaCaTs is dependent on ?4 integrin, and ?6 integrin processing. Virology 449:45-52