Human Polyomavirus JC monitoring and noncoding control region analysis in dynamic cohorts of individuals affected by immune-mediated diseases under treatment with biologics: an observational study.
BACKGROUND
Progressive multifocal leukoencephalopathy (PML) onset, caused by Polyomavirus JC (JCPyV) in patients affected by immune-mediated diseases during biological treatment, raised concerns about the safety profile of these agents. Therefore, the aims of this study were the JCPyV reactivation monitoring and the noncoding control region (NCCR) and viral protein 1 (VP1) analysis in patients affected by different immune-mediated diseases and treated with biologics.


METHODS
We performed JCPyV-specific quantitative PCR of biological samples collected at moment of recruitment (t0) and every 4 months (t1, t2, t3, t4). Subsequently, rearrangements' analysis of NCCR and VP1 was carried out. Data were analyzed using χ2 test.


RESULTS
Results showed that at t0 patients with chronic inflammatory rheumatic diseases presented a JCPyV load in the urine significantly higher (p≤0.05) than in patients with multiple sclerosis (MS) and Crohn's disease (CD). It can also be observed a significant association between JC viruria and JCPyV antibodies after 1 year of natalizumab (p=0.04) in MS patients. Finally, NCCR analysis showed the presence of an archetype-like sequence in all urine samples, whereas a rearranged NCCR Type IR was found in colon-rectal biopsies collected from 2 CD patients after 16 months of infliximab. Furthermore, sequences isolated from peripheral blood mononuclear cells (PBMCs) of 2 MS patients with JCPyV antibody at t0 and t3, showed a NCCR Type IIR with a duplication of a 98 bp unit and a 66 bp insert, resulting in a boxB deletion and 37 T to G transversion into the Spi-B binding site. In all patients, a prevalence of genotypes 1A and 1B, the predominant JCPyV genotypes in Europe, was observed.


CONCLUSIONS
It has been important to understand whether the specific inflammatory scenario in different immune-mediated diseases could affect JCPyV reactivation from latency, in particular from kidneys. Moreover, for a more accurate PML risk stratification, testing JC viruria seems to be useful to identify patients who harbor JCPyV but with an undetectable JCPyV-specific humoral immune response. In these patients, it may also be important to study the JCPyV NCCR rearrangement: in particular, Spi-B expression in PBMCs could play a crucial role in JCPyV replication and NCCR rearrangement.
Department of Public Health and Infectious Diseases, Sapienza University, P,le Aldo Moro, 5, 00185 Rome, Italy. valeria.pietropaolo@uniroma1.it.
Anna
A
Bellizzi
Elena
E
Anzivino
Donatella Maria
DM
Rodio
Sara
S
Cioccolo
Rossana
R
Scrivo
Manuela
M
Morreale
Simona
S
Pontecorvo
Federica
F
Ferrari
Giovanni
G
Di Nardo
Lucia
L
Nencioni
Silvia
S
Carluccio
Guido
G
Valesini
Ada
A
Francia
Salvatore
S
Cucchiara
Anna Teresa
AT
Palamara
Valeria
V
Pietropaolo
D000328:Adult; D001688:Biological Products / Q000627:therapeutic use*; D003106:Colon / Q000821:virology; D021901:DNA, Intergenic; D005260:Female; D005838:Genotype; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy* / Q000821:virology*; D007577:JC Virus / Q000235:genetics* / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D011995:Recombination, Genetic; D014556:Urine / Q000821:virology; D019562:Viral Load; D015678:Viral Structural Proteins / Q000235:genetics; D014775:Virus Activation
D001688:Biological Products; D021901:DNA, Intergenic; D015678:Viral Structural Proteins