Journal Article

Sequencing and Analysis of JC Virus DNA From Natalizumab-Treated PML Patients

Carmillo, Paul, McAuliffe, Michele, Gorelik, Leonid, Tizard, Rich, Sur, Gargi, Simon, Kenneth, Cinque, Paola, Li, Huo, Goelz, Susan, Bushnell, Steven, Carulli, John P., Reid, Carl E., Tonkin, Christopher

2011

Overview

Background. Progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients is linked to JC virus (JCV) infection. JCV sequence variation and rearrangements influence viral pathogenicity and tropism. To better understand PML development, we analyzed viral DNA sequences in blood, CSF and/or urine of natalizumabtreated PML patients. Methods. Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding region, and the entire 5 kb viral genome. Results. Analysis of JCV from multiple biofluids revealed that individuals were infected with a single genotype. Across our patient cohort, multiple PML-associated NCCR rearrangements and VP1 mutations were present in CSF and blood, but absent from urine-derived virus. NCCR rearrangements occurred in CSF of 100% of our cohort. VP1 mutations were observed in blood or CSF in 81% of patients. Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could occur without VPl mutations, but VP1 mutations were not observed without NCCR rearrangement. Conclusions. These data confirm that JCV in natalizumab-PML patients is similar to that observed in other PML patient groups, multiple genotypes are associated with PML, individual patients appear to be infected with a single genotype, and PML-associated mutations arise in patients during PML development.

• Publisher: Oxford University Press
• Subject: Amino Acid Substitution - genetics / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal, Humanized / Archetypes / Biological and medical sciences / Blood - virology / Capsid Proteins - genetics / Cerebrospinal fluid / DNA, Viral - chemistry / DNA, Viral - genetics / Fundamental and applied biological sciences. Psychology / Genetic mutation / Genomes / Genotypes / Humans / Immunologic Factors - administration & dosage / Infectious diseases / JC virus / JC Virus - genetics / JC Virus - isolation & purification / Leukoencephalopathy, Progressive Multifocal - drug therapy / Leukoencephalopathy, Progressive Multifocal - virology / Major and Brief Reports / Medical sciences / Microbiology / Miscellaneous / Mutation, Missense / Natalizumab / Polymerase chain reaction / Progressive multifocal leukoencephalopathy / Sequence Analysis, DNA / Urine / Virology / Viruses