Our overall goal is to characterize the immune response to HPV infection for two distinct purposes: first, to identify serological markers that are correlated with a) HPV infection; b) protection in preventing the development or spread of anogenital cancers; or c) that are prognostic indicators of invasion or metastasis; and second, to understand the immune response to HPV to design immunotherapeutic strategies. We developed a first generation of reagents and techniques that allowed the initial identification of antibodies to a variety of HPV 6 and 16 proteins in human sera. The use of bacterially expressed fusion proteins in Western blot assays was particularly informative in studying antibodies to the E7 protein. We have also used yeast-expressed E7 in an ELISA and will continue to study responses to that tumor associated antigen. Recently we produced HPV capsids using vaccinia recombinants and have shown that the major capsid protein, L1, with or without L2, self-assembles to form capsids that are structurally identical to authentic virions. We have developed a sandwich ELISA using monoclonal antibodies to L1 to capture the capsid particles, and have detected antibodies in human sera that recognize a conformational epitope(s) on the native HPV particle. Most interestingly these antibodies correlate significantly with a history of HPV infection. An important goal will be to determine whether capsid antibodies are related to anogenital cancers. We have established collaborations to begin to examine the cell mediated immune response to HPV infection and the role of the host HLA genotype in the immune response. The goals of this funding period are to continue to examine the relationship between serological markers and the development of anogenital malignancies, and to expand our studies to look for T cell responses and to characterize the HLA type in our populations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA042792-10
Application #
5207350
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
1996
Total Cost
Indirect Cost
Bao, Xiao; Hanson, Aimee L; Madeleine, Margaret M et al. (2018) HLA and KIR Associations of Cervical Neoplasia. J Infect Dis 218:2006-2015
Leo, Paul J; Madeleine, Margaret M; Wang, Sophia et al. (2017) Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study. PLoS Genet 13:e1006866
Wallace, Nicholas A; Khanal, Sujita; Robinson, Kristin L et al. (2017) High-Risk Alphapapillomavirus Oncogenes Impair the Homologous Recombination Pathway. J Virol 91:
Madeleine, Margaret M; Johnson, Lisa G; Doody, David R et al. (2016) Natural Antibodies to Human Papillomavirus 16 and Recurrence of Vulvar High-Grade Intraepithelial Neoplasia (VIN3). J Low Genit Tract Dis 20:257-60
Hardikar, Sheetal; Johnson, Lisa G; Malkki, Mari et al. (2015) A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers. Gynecol Oncol 139:90-6
Wallace, Nicholas A; Robinson, Kristin; Howie, Heather L et al. (2015) ?-HPV 5 and 8 E6 disrupt homology dependent double strand break repair by attenuating BRCA1 and BRCA2 expression and foci formation. PLoS Pathog 11:e1004687
Galloway, Denise A; Laimins, Laimonis A (2015) Human papillomaviruses: shared and distinct pathways for pathogenesis. Curr Opin Virol 14:87-92
Wallace, Nicholas A; Galloway, Denise A (2014) Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses. Semin Cancer Biol 26:30-42
Wallace, Nicholas A; Robinson, Kristin; Galloway, Denise A (2014) Beta human papillomavirus E6 expression inhibits stabilization of p53 and increases tolerance of genomic instability. J Virol 88:6112-27
Bodelon, Clara; Madeleine, Margaret M; Johnson, Lisa G et al. (2014) Genetic variation in the TLR and NF-?B pathways and cervical and vulvar cancer risk: a population-based case-control study. Int J Cancer 134:437-44

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