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Updated: Jun 1, 2026
VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma
Published on: December 28, 2015
Sequencing and analysis of JC virus DNA from natalizumab-treated PML patients
Carl E Reid1, Huo Li, Gargi Sur
1Biogen Idec Inc., Cambridge, MA 02142, USA. carl.reid@biogenidec.com
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 natalizumab-treated 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 VP1 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.
Insights
JC virus (JCV) mutations and rearrangements in the noncoding control region (NCCR) are associated with progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients. These changes arise during PML development, indicating viral evolution.
Area of Science:
- Neurovirology
- Molecular Virology
- Immunology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infection linked to JC virus (JCV) in natalizumab-treated multiple sclerosis (MS) patients.
- JCV sequence variations and genomic rearrangements are known to influence viral pathogenicity and tropism, playing a role in PML development.
Purpose of the Study:
- To investigate the JCV sequence variations, including noncoding control region (NCCR) rearrangements and VP1 capsid coding region mutations, in natalizumab-treated PML patients.
- To understand the relationship between viral genotypes, mutations, and PML development by analyzing JCV DNA from various biofluids.
Main Methods:
- Sequencing of multiple JCV isolates from blood, cerebrospinal fluid (CSF), and/or urine samples of 17 natalizumab-treated PML patients.
- Analysis focused on the JCV NCCR, VP1 capsid coding region, and the complete viral genome (5 kb).
Main Results:
- Individuals were infected with a single JCV genotype, but multiple PML-associated NCCR rearrangements and VP1 mutations were detected in CSF and blood, though not in urine.
- NCCR rearrangements were found in the CSF of 100% of the cohort, and VP1 mutations were present in blood or CSF in 81% of patients.
- Complete genome sequencing revealed that NCCR rearrangements could occur independently, but VP1 mutations were always associated with NCCR rearrangement.
Conclusions:
- JCV found in natalizumab-associated PML patients shares similarities with JCV from other PML patient groups.
- Multiple JCV genotypes are associated with PML, although individual patients are typically infected with a single genotype.
- PML-associated JCV mutations and NCCR rearrangements arise during the course of PML development in patients.
