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Gene Expression Patterns Induced by HPV-16 L1 Virus-Like Particles in Leukocytes from Vaccine Recipients

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Gene Expression Patterns Induced by HPV-16 L1 Virus-Like Particles in Leukocytes from Vaccine Recipients Gene Expression Patterns Induced by HPV-16 L1 Virus-Like Particles in Leukocytes from Vaccine Recipients This information is current as Alfonso J. García-Piñeres, Allan Hildesheim, Lori Dodd, of October 3, 2021. Troy J. Kemp, Jun Yang, Brandie Fullmer, Clayton Harro, Douglas R. Lowy, Richard A. Lempicki and Ligia A. Pinto J Immunol 2009; 182:1706-1729; ; doi: 10.4049/jimmunol.182.3.1706 http://www.jimmunol.org/content/182/3/1706 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2009/01/15/182.3.1706.DC1 Material http://www.jimmunol.org/ References This article cites 53 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/182/3/1706.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 3, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Gene Expression Patterns Induced by HPV-16 L1 Virus-Like Particles in Leukocytes from Vaccine Recipients1 Alfonso J. García-Pin˜eres,2* Allan Hildesheim,† Lori Dodd,‡ Troy J. Kemp,* Jun Yang,§ Brandie Fullmer,§ Clayton Harro,¶ Douglas R. Lowy,ʈ Richard A. Lempicki,§ and Ligia A. Pinto3* Human papillomavirus (HPV) virus-like particle (VLP) vaccines were recently licensed. Although neutralizing Ab titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMCs from 17 vaccine and 4 placebo recipients before vaccination and 1 mo after receiving the second immunization. Vaccination with a monovalent HPV-16 L1 VLP vaccine was associated with modulation of genes involved in the inflammatory/defense response, cytokine, IFN, and cell cycle pathways in Downloaded from VLP-stimulated PBMCs. Additionally, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing Ab titers were found for cyclin D2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an inde- pendent sample set. Agreement with microarray data was seen for more than two-thirds of these probesets. Up-regulation of immune/defense response genes by HPV-16 L1 VLP, in particular, IFN-induced genes, was observed in PBMCs collected before vaccination, with many of these genes being further induced following vaccination. In conclusion, we identified important innate http://www.jimmunol.org/ and adaptive response-related genes induced by vaccination with HPV-16 L1 VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vacci- nation outcomes in clinical trials. The Journal of Immunology, 2009, 182: 1706–1729. ervical cancer is the second most common cancer among moral response has been observed after vaccination (8–10), and women worldwide (1, 2). The recent development of pro- Ab levels against HPV-16 remain relatively high in the first few C phylactic human papillomavirus (HPV)4 vaccines pro- years after vaccination (11–13). However, length of protection af- vides an important new avenue for the prevention of this cancer forded by vaccination is not currently known. and others linked to HPV infection. Studies by our group and others have shown that in addition to by guest on October 3, 2021 The current HPV prophylactic vaccines consist of noninfectious, Ab responses, strong cell-mediated immune responses are ob- L1 recombinant HPV-like particles (VLP) (3, 4). Vaccine clinical served after vaccination (14–17). It is known that cell-mediated trials have shown nearly complete protection against cervical in- immune responses are required for Ab production and for main- traepithelial neoplasia 2 or greater lesions (5–7). Neutralizing Abs tenance of Ab levels over time. Thus, it could be postulated that are thought to be the main effectors of protection. A robust hu- the patterns of innate and acquired cellular immune responses fol- lowing initial vaccination might influence Ab responses and du- *HPV Immunology Laboratory, Science Applications International Corporation ration of protection afforded by vaccination (18, 19). A better un- (SAIC)-Frederick/National Cancer Institute (NCI)-Frederick, Frederick, MD 21702; derstanding of these early responses to vaccination might help † ‡ Division of Cancer Epidemiology and Genetics and Biometric Research Branch, elucidate mechanisms of vaccine protection via neutralizing Abs, Division of Cancer Treatment and Diagnosis, National Institutes of Health, Bethesda, MD 20892; §Laboratory of Bioinformatics and Immunopathogenesis, SAIC-Freder- and assist in the identification of early markers of long-lasting ick/NCI-Frederick, Frederick, MD 21702; ¶Center for Immunization Research, Johns vaccine responses. Hopkins University, Baltimore, MD 21205; and ʈCenter for Cancer Research, Na- tional Institutes of Health, Bethesda, MD 20814 Microarray analysis has been applied to determine gene expres- Received for publication July 17, 2008. Accepted for publication November 17, 2008. sion patterns in studies of disease pathogenesis (20–23), immune response to infection (24–30), and immune response after immu- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance nization (31, 32). However, few studies have looked at vaccine- with 18 U.S.C. Section 1734 solely to indicate this fact. induced responses in humans (33–35). 1 This project has been funded in whole or in part with Federal funds from the Na- To characterize the immune response to HPV-16 L1 VLP vac- tional Cancer Institute, National Institutes of Health (N01-CO-12400). cination, we used microarray chips that cover 8638 verified se- The content of this publication does not necessarily reflect the views or policies of the quences to investigate the gene profile associated with a recall Department of Health and Human Services, nor does mention of trade names, com- mercial products, or organizations imply endorsement by the U.S. Government. response to the vaccine in leukocytes from vaccine recipients. We 2 Current address: Escuela de Química, Universidad de Costa Rica, San Jose´, Costa identified probesets that were differentially expressed in PBMCs Rica. from vaccine recipients after in vitro stimulation with HPV-16 L1 3 Address correspondence and reprint requests to Dr. Ligia A. Pinto, Science Appli- VLP compared with pre-vaccination samples. We also analyzed cations International Corporation (SAIC)-Frederick/National Cancer Institute (NCI)- the “primary” response to HPV-16 L1 VLP, independent of vac- Frederick, Building 469, Room 120, Frederick, MD 21702. E-mail address: [email protected] cination, by comparing the gene expression pattern of cells incu- 4 Abbreviations used in this paper: HPV, human papillomavirus; ds-cDNA, double- bated with HPV-16 L1 VLP and unstimulated cells, using prevac- stranded cDNA; RPLPO, ribosomal protein, large P0; VLP, virus-like particles. cination samples. www.jimmunol.org The Journal of Immunology 1707 Additionally, the correlation of gene expression to neutralizing microcapillary electrophoresis using the Agilent 2100 bioanalyzer (Agilent Ab titers developed after vaccination was examined to evaluate Technologies). potential determinants of strong Ab responses. Key results were Microarray gene expression analysis was performed using the human genome focus array from the Affymetrix GeneChip system (Affymetrix) confirmed by RT-PCR in an independent set of vaccinated that contains ϳ8700 probesets to 8638 characterized human genes. Total individuals. RNA preparation and labeled cRNA synthesis and hybridization were per- This is the first study that evaluates the immune response to an formed according to the manufacturer’s recommended protocol (Af- HPV VLP vaccine using microarray technology. Our results con- fymetrix). In short, 10 ␮g of total RNA was used for double-stranded cDNA (ds-cDNA) synthesis with the SuperScript II reverse transcriptase tribute to a broader understanding of the effects of vaccination with kit (Invitrogen) and an oligo(dT) primer containing a T7 RNA polymerase a monovalent HPV-16 L1 VLP vaccine. The approach used herein promoter to prime the first-strand synthesis. Biotin-labeled cRNA was ob- and the gene expression profile defined in this study may prove to tained by in vitro transcription after addition of T7 RNA polymerase and be useful for future prediction of long-term HPV vaccination out- biotinylated
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