title: Polyomavirus JC reactivation and noncoding control region sequence analysis in pediatric Crohn's disease patients treated with infliximab.
abstract: The recent introduction of monoclonal antibodies in Crohn's disease (CD) management has been associated with the development of serious complications, such as the progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus (JCV) reactivation. Therefore, the aims of our study have been the investigation of the possible JCV reactivation in pediatric CD patients treated or not with infliximab, performing quantitative PCR in urine, plasma, and intestinal biopsies at the time of recruitment (t0) and every 4 months in 1 year of follow-up (t1, t2, and t3), and the analysis of the JCV noncoding control region (NCCR) to detect cellular transcription factors binding site mutations. Results obtained showed that, in urine and ileal specimens, JCV load significantly increased in infliximab-treated patients after 1 year of treatment (t3), while viremia was significantly higher at t1. JCV NCCR sequence analysis showed a structure similar to CY archetype in 65/80 analyzed sequences, but the remaining 15/80, obtained exclusively from plasma and biopsies, evidenced a CY NCCR organization with two recurrent nucleotide changes, the 37-T to G transversion in box A Spi-B binding site and the 217-G to A transition in box F, and a box D deletion. These rearrangements were always found at t3 within seven infliximab-treated CD patients, who presented a very severe disease at t0. We can conclude that our rearranged NCCR sequences could be considered a marker of JCV virulence during mAb treatment, although none of our examined patients developed PML, and further studies on a larger cohort of patients should be performed.
authors.affiliation: Department of Health Sciences and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bellizzi
authors.forename: Elena
authors.initials: E
authors.lastname: Anzivino
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Nardo
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Colosimo
authors.forename: Daniela
authors.initials: D
authors.lastname: Fioriti
authors.forename: Monica
authors.initials: M
authors.lastname: Mischitelli
authors.forename: Fernanda
authors.initials: F
authors.lastname: Chiarini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.forename: Valeria
authors.initials: V
authors.lastname: Pietropaolo
mesh_terms: D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D003424:Crohn Disease / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D004279:DNA, Viral / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000069285:Infliximab; D007577:JC Virus / Q000235:genetics / Q000472:pathogenicity; D007968:Leukoencephalopathy, Progressive Multifocal / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014775:Virus Activation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D004279:DNA, Viral; D000069285:Infliximab