JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

Emilie Sundqvist, Dorothea Buck, Clemens Warnke, Eva Albrecht, Christian Gieger, Mohsen Khademi, Izaura Lima Bomfim, Anna Fogdell-Hahn, Jenny Link, Lars Alfredsson, Helle Bach Søndergaard, Jan Hillert, Lisa Barcellos, David Booth, Jacob L McCauley, Manuel Comabella, Alastair Compston, Sandra DAlfonso, Philip De Jager, Bertrand Fontaine & 26 others An Goris, David Hafler, Jonathan Haines, Hanne F. Harbo, Stephen L. Hauser, Clive Hawkins, Bernhard Hemmer, Jan Hillert, Adrian Ivinson, Ingrid Kockum, Roland Martin, Filippo Martinelli Boneschi, Jorge Oksenberg, Tomas Olsson, Annette Oturai, Nikolaos Patsopoulos, Margaret A Pericak-Vance, Janna Saarela, Stephen Sawcer, Anne Spurkland, Graeme Stewart, Frauke Zipp, Annette B. Oturai, Bernhard Hemme, Ingrid Kockum, Tomas Olsson

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

Original languageEnglish
Article numbere1004084
JournalPLoS Pathogens
Volume10
Issue number4
DOIs
StatePublished - Jan 1 2014

Fingerprint

Polyomavirus Infections
JC Virus
HLA Antigens
Haplotypes
Progressive Multifocal Leukoencephalopathy
Alleles
Antibody Formation
Antibodies
Integrin alpha4beta1
T-Lymphocytes
Genome-Wide Association Study
Oligodendroglia
Infection Control
Oligonucleotides

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Sundqvist, E., Buck, D., Warnke, C., Albrecht, E., Gieger, C., Khademi, M., ... Olsson, T. (2014). JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants. PLoS Pathogens, 10(4), [e1004084]. https://doi.org/10.1371/journal.ppat.1004084

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants. / Sundqvist, Emilie; Buck, Dorothea; Warnke, Clemens; Albrecht, Eva; Gieger, Christian; Khademi, Mohsen; Lima Bomfim, Izaura; Fogdell-Hahn, Anna; Link, Jenny; Alfredsson, Lars; Søndergaard, Helle Bach; Hillert, Jan; Barcellos, Lisa; Booth, David; McCauley, Jacob L; Comabella, Manuel; Compston, Alastair; DAlfonso, Sandra; De Jager, Philip; Fontaine, Bertrand; Goris, An; Hafler, David; Haines, Jonathan; Harbo, Hanne F.; Hauser, Stephen L.; Hawkins, Clive; Hemmer, Bernhard; Hillert, Jan; Ivinson, Adrian; Kockum, Ingrid; Martin, Roland; Boneschi, Filippo Martinelli; Oksenberg, Jorge; Olsson, Tomas; Oturai, Annette; Patsopoulos, Nikolaos; Pericak-Vance, Margaret A; Saarela, Janna; Sawcer, Stephen; Spurkland, Anne; Stewart, Graeme; Zipp, Frauke; Oturai, Annette B.; Hemme, Bernhard; Kockum, Ingrid; Olsson, Tomas.

In: PLoS Pathogens, Vol. 10, No. 4, e1004084, 01.01.2014.

Research output: Contribution to journalArticle

Sundqvist, E, Buck, D, Warnke, C, Albrecht, E, Gieger, C, Khademi, M, Lima Bomfim, I, Fogdell-Hahn, A, Link, J, Alfredsson, L, Søndergaard, HB, Hillert, J, Barcellos, L, Booth, D, McCauley, JL, Comabella, M, Compston, A, DAlfonso, S, De Jager, P, Fontaine, B, Goris, A, Hafler, D, Haines, J, Harbo, HF, Hauser, SL, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Kockum, I, Martin, R, Boneschi, FM, Oksenberg, J, Olsson, T, Oturai, A, Patsopoulos, N, Pericak-Vance, MA, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Oturai, AB, Hemme, B, Kockum, I & Olsson, T 2014, 'JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants', PLoS Pathogens, vol. 10, no. 4, e1004084. https://doi.org/10.1371/journal.ppat.1004084
Sundqvist E, Buck D, Warnke C, Albrecht E, Gieger C, Khademi M et al. JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants. PLoS Pathogens. 2014 Jan 1;10(4). e1004084. https://doi.org/10.1371/journal.ppat.1004084
Sundqvist, Emilie ; Buck, Dorothea ; Warnke, Clemens ; Albrecht, Eva ; Gieger, Christian ; Khademi, Mohsen ; Lima Bomfim, Izaura ; Fogdell-Hahn, Anna ; Link, Jenny ; Alfredsson, Lars ; Søndergaard, Helle Bach ; Hillert, Jan ; Barcellos, Lisa ; Booth, David ; McCauley, Jacob L ; Comabella, Manuel ; Compston, Alastair ; DAlfonso, Sandra ; De Jager, Philip ; Fontaine, Bertrand ; Goris, An ; Hafler, David ; Haines, Jonathan ; Harbo, Hanne F. ; Hauser, Stephen L. ; Hawkins, Clive ; Hemmer, Bernhard ; Hillert, Jan ; Ivinson, Adrian ; Kockum, Ingrid ; Martin, Roland ; Boneschi, Filippo Martinelli ; Oksenberg, Jorge ; Olsson, Tomas ; Oturai, Annette ; Patsopoulos, Nikolaos ; Pericak-Vance, Margaret A ; Saarela, Janna ; Sawcer, Stephen ; Spurkland, Anne ; Stewart, Graeme ; Zipp, Frauke ; Oturai, Annette B. ; Hemme, Bernhard ; Kockum, Ingrid ; Olsson, Tomas. / JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants. In: PLoS Pathogens. 2014 ; Vol. 10, No. 4.
@article{9680dc9dc40e4e8b9179c81d6d24d9f1,
title = "JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants",
abstract = "JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60{\%} of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.",
author = "Emilie Sundqvist and Dorothea Buck and Clemens Warnke and Eva Albrecht and Christian Gieger and Mohsen Khademi and {Lima Bomfim}, Izaura and Anna Fogdell-Hahn and Jenny Link and Lars Alfredsson and S{\o}ndergaard, {Helle Bach} and Jan Hillert and Lisa Barcellos and David Booth and McCauley, {Jacob L} and Manuel Comabella and Alastair Compston and Sandra DAlfonso and {De Jager}, Philip and Bertrand Fontaine and An Goris and David Hafler and Jonathan Haines and Harbo, {Hanne F.} and Hauser, {Stephen L.} and Clive Hawkins and Bernhard Hemmer and Jan Hillert and Adrian Ivinson and Ingrid Kockum and Roland Martin and Boneschi, {Filippo Martinelli} and Jorge Oksenberg and Tomas Olsson and Annette Oturai and Nikolaos Patsopoulos and Pericak-Vance, {Margaret A} and Janna Saarela and Stephen Sawcer and Anne Spurkland and Graeme Stewart and Frauke Zipp and Oturai, {Annette B.} and Bernhard Hemme and Ingrid Kockum and Tomas Olsson",
year = "2014",
month = "1",
day = "1",
doi = "10.1371/journal.ppat.1004084",
language = "English",
volume = "10",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

AU - Sundqvist, Emilie

AU - Buck, Dorothea

AU - Warnke, Clemens

AU - Albrecht, Eva

AU - Gieger, Christian

AU - Khademi, Mohsen

AU - Lima Bomfim, Izaura

AU - Fogdell-Hahn, Anna

AU - Link, Jenny

AU - Alfredsson, Lars

AU - Søndergaard, Helle Bach

AU - Hillert, Jan

AU - Barcellos, Lisa

AU - Booth, David

AU - McCauley, Jacob L

AU - Comabella, Manuel

AU - Compston, Alastair

AU - DAlfonso, Sandra

AU - De Jager, Philip

AU - Fontaine, Bertrand

AU - Goris, An

AU - Hafler, David

AU - Haines, Jonathan

AU - Harbo, Hanne F.

AU - Hauser, Stephen L.

AU - Hawkins, Clive

AU - Hemmer, Bernhard

AU - Hillert, Jan

AU - Ivinson, Adrian

AU - Kockum, Ingrid

AU - Martin, Roland

AU - Boneschi, Filippo Martinelli

AU - Oksenberg, Jorge

AU - Olsson, Tomas

AU - Oturai, Annette

AU - Patsopoulos, Nikolaos

AU - Pericak-Vance, Margaret A

AU - Saarela, Janna

AU - Sawcer, Stephen

AU - Spurkland, Anne

AU - Stewart, Graeme

AU - Zipp, Frauke

AU - Oturai, Annette B.

AU - Hemme, Bernhard

AU - Kockum, Ingrid

AU - Olsson, Tomas

PY - 2014/1/1

Y1 - 2014/1/1

N2 - JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

AB - JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

UR - http://www.scopus.com/inward/record.url?scp=84901344743&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901344743&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1004084

DO - 10.1371/journal.ppat.1004084

M3 - Article

VL - 10

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 4

M1 - e1004084

ER -