Regulation of Human Papillomavirus Replication via Cell Signaling Pathways

Summary

Principal Investigator: ANASTACIA GRIEGO
Abstract: DESCRIPTION (provided by applicant): Human papillomaviruses (HPVs) are small double-stranded DNA viruses that are highly species specific and possess a strict tropism for squamous epithelium. Over 150 HPV types are capable of infecting mucosal and cutaneous epithelium, the majority of these types cause only benign lesions such as warts. HPVs are designated as oncogenic based on the ability of a specific viral genotype to cause transformation in the host cell. Of the oncogenic types, HPV-16 and HPV-18 together cause over 60% of cervical cancers and HPV-16 is associated with 72% of HPV[+] oropharyngeal squamous cell carcinomas (OSCCs). Although prophylactic vaccines are very effective in preventing infection by HPV-16 and HPV-18, the uptake of the vaccines is poor in the US and many millions of people are already HPV infected. Further, HPV[+] OSCC incidence is rising. The current heavy burden of HPV-related infections and diseases, as well as the morbidity and/or underachievement of current therapies, underscores the need for development of efficacious therapeutic strategies. Early proteins E5, E6, And E7 from oncogenic HPV types are known to regulate epidermal growth factor receptor (EGFR) gene transcription and recycling in infected cells. Based on previous studies indicating AP-1 transcription factors regulate HPV gene expression, we hypothesize that HPV infection establishes an intracellular feed-forward loop with the EGFR signaling pathway that does not require high levels of EGFR expression. We posit that HPV-mediated gene expression results in increased EGFR signal transduction leading to enhanced viral transcription through modulation of cell survival and proliferation signals. Specific Aims are designed to determine if initiating a break in EGFR-pathway signaling will result in down regulation of HPV activities in infected cells, leading to recovered p53 and pRb activity, which could render cells more susceptible to chemotherapy and radiation. We expect to determine how AP-1 transcription factors regulate HPV replication in infected cells that maintain episomal or integrated viral genomes. We will use genetic and biochemical assays coupled with quantitative measures of viral replication and cell proliferation and viability. These are cutting-edge approaches and will evaluate the ability of EGFR-pathway inhibitors to decrease viral activities in human keratinocytes containing episomal or integrated high-risk HPVs. Our scientific expertise in HPV biology and cancer research makes us uniquely suited to carry out this work. Understanding the mechanism of the inhibitors effect on viral transcription and genome maintenance may lead to the development of more efficacious therapeutic strategies. Additionally, we will have learned critical aspects of the interplay between host and virus that may underlie progression to cancer and/or prognosis of HPV[+] lesions.
Funding Period: -----------------201 - ----------------2016
more information: NIH RePORT

Research Grants

  1. STATISTICAL METHODS FOR MEDICAL STUDIES
    Ross L Prentice; Fiscal Year: 2013
  2. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
  3. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
  4. TCR Gene Modified T Cells for Adoptive Immunotherapy
    Michael I Nishimura; Fiscal Year: 2013
  5. Entry of Oncogenic HPVs into Human Keratinocytes
    Michelle A Ozbun; Fiscal Year: 2013
  6. Perturbation of a cellular microRNA by human papillomavirus type 16.
    MALLORY ELLEN HARDEN; Fiscal Year: 2013
  7. Therapeutic vaccination against genital HPV infection
    Yung Nien Chang; Fiscal Year: 2013
  8. HPV-16 and head and neck cancer
    Thomas Haugen; Fiscal Year: 2013
  9. MODULATION OF HOST CELL APOPTOTIC RESPONSES BY HPVE7
    Karl Munger; Fiscal Year: 2013
  10. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013

Detail Information

Research Grants30

  1. STATISTICAL METHODS FOR MEDICAL STUDIES
    Ross L Prentice; Fiscal Year: 2013
    ..abstract_text> ..
  2. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
    ..The program represents an integrated effort to improve screening with the overall aim of averting deaths from breast cancer while minimizing harms. ..
  3. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
    ..The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease. ..
  4. TCR Gene Modified T Cells for Adoptive Immunotherapy
    Michael I Nishimura; Fiscal Year: 2013
    ..abstract_text> ..
  5. Entry of Oncogenic HPVs into Human Keratinocytes
    Michelle A Ozbun; Fiscal Year: 2013
    ..Our findings will also provide significant insight into receptor-mediated endocytosis in keratinocytes, an area vastly understudied. ..
  6. Perturbation of a cellular microRNA by human papillomavirus type 16.
    MALLORY ELLEN HARDEN; Fiscal Year: 2013
    ..Lastly, aim 3 is to address the role of miR-34a in the HPV16 lifecycle. Through studying this miR, a greater understanding of how HPVs cause cancer will be elucidated. ..
  7. Therapeutic vaccination against genital HPV infection
    Yung Nien Chang; Fiscal Year: 2013
    ..These preclinical studies will drive future Papivax-driven clinical trials of therapeutic vaccines to eliminate persistent HPV infections. ..
  8. HPV-16 and head and neck cancer
    Thomas Haugen; Fiscal Year: 2013
    ..How does E1 expression contribute to establishment of viral persistence? 3. How does E2 expression contribute to establishment of viral persistence? ..
  9. MODULATION OF HOST CELL APOPTOTIC RESPONSES BY HPVE7
    Karl Munger; Fiscal Year: 2013
    ..abstract_text> ..
  10. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..
  11. Center for the Study of Innate Immunity to HCV Infection
    Michael J Gale; Fiscal Year: 2013
    ..Our studies are linked with the U19 Clinical Core, and Projects 2 and 3 to feature translational approaches aimed at defining the virus-host interface that controls hepatic innate immunity and HCV infection. ..
  12. Virus-Host Interactions that Modulate Early Steps of Human Papillomavirus Infecti
    Dohun Pyeon; Fiscal Year: 2013
    ..The goals of our research are to understand the mechanisms of HPV-host interactions necessary for establishing and maintaining HPV infections in primary keratinocytes in vitro and in vivo. ..
  13. MECHANISMS OF HUMAN PAPILLOMAVIRUS DNA REPLICATION
    Louise T Chow; Fiscal Year: 2013
    ..With a thorough understanding of the pathways which HPVs dysregulate and to which HPVs are addicted, targets of therapeutic agents will be identified to serve as the foundation for antiviral drug discovery. ..
  14. INTERACTIONS OF HPV ONCOGENES WITH THE P53 PATHWAY
    Denise A Galloway; Fiscal Year: 2013
    ..Secondly, we will explore the new finding that TERT associates with RMRP RNA, which is processed into siRNAs. We will test the hypothesis that siRNAs generated by this complex regulate critical features of HPV expressing cells. ..
  15. Model-based predictions of responses RTK Pathway therapies
    Joe W Gray; Fiscal Year: 2013
    ..abstract_text> ..
  16. Small Molecule Screen Targeting p53 proteolysis in HPV positive cancers
    Peter M Howley; Fiscal Year: 2013
    ....
  17. E2-Cellular Complexes in HPV Chromatin Transcription
    Cheng Ming Chiang; Fiscal Year: 2013
    ....
  18. M.D. Anderson Gynecologic SPORE for Uterine Cancers
    KAREN HSIEH LU; Fiscal Year: 2013
    ..Four Cores will support these projects. Core A (Administrative Core), Core B (Pathology Core), Core C Biomarkers Core, and Core D (Biostatistics and Bioinformatics Core). ..