Human papillomaviruses (HPVs) are composed of relatively small circular, double-stranded DNA genomes within icosahedral capsids. Among the over 100 HPV strains identified so far, approximately 40 genotypes are associated with genital diseases. HPV infection is generally asymptomatic and doesn't cause disease. However, if the virus genome is maintained at a low level termed latency and evades immune recognition, HPV may lead to abnormal cell changes and severe diseases. The HPVs that infect genital tract could be divided into two groups, based on their oncogenic potential and association with cancer development. The low-risk HPVs cause genital warts, and seldom linked to tumorigenesis. However, some high-risk HPVs (such as HPV16) have been well recognized as the causative agents of cervical cancer and as cofactors for several other epithelial cancer types. Currently, the two HPV vaccines can only target limited oncogenic HPVs and are not affordable in all the countries. During HPV entry, heparan sulfate proteoglycans (HSPGs) serve as the attachment factor to increase efficiency of HPV infection. Binding to HSPGs leads to the conformational change in the viral particles and cleavage of capsid protein L2, followed by the interaction of virion with a secondary unidentified entry receptor. HPV particles enter cells mainly through endocytosis in a strain and cell type dependent manner, and disassembly of virus particle occurs in endosomes at low pH. Cytoskeleton has been suggested to be involved in HPV intracellular trafficking. The poor understanding of entry and trafficking mechanism of HPV has restrained the development of new vaccines and anti-viral drugs. The genome-wide siRNA screen found gamma-secretase (J-sec) as an essential factor for HPV16 infection in epithelial cells, although the mechanism is not well characterized. This project will investigate the function of J-sec and its substrate(s) during the infectious route of HPV16 into human epithelial cells.
The first aim of this study will examine the critical steps that require J-sec duing HPV16 infection by specifically measuring virus disassembly and the localization of virus particles with newly developed technologies. The steps that are inhibited by loss of J-sec activity will be investigated in relation to various cell markers. The second part of this research will examine the role of two potential substrates of J-sec in mediating HPV16 entry by proposed models.
This aim may provide a mechanistic understanding of the absolute requirement of J-sec on HPV entry. Overall, the proposed aims will be valuable for the understanding of HPV16 entry process and the design of new targets for antiviral therapies.

Public Health Relevance

The human papillomavirus (HPV) is the most common viral sexually transmitted infection all over the world. High-risk oncogenic HPVs (such as HPV16) are identified in most cervical cancer and some other types of cancers, all of which accounts for 5% of all human cancers. The two HPV vaccines in market only provide partial protection against pathogenic HPVs and the cost and storage of vaccines are burdens in developing countries. This proposal research will significantly improve our understanding of the mechanisms utilized by HPVs to infect cells and facilitate the development of vaccines and anti-viral drugs.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI114132-01
Application #
8783864
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Park, Eun-Chung
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510