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 FontaineAn 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 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

24 Scopus citations

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 (US)
Article numbere1004084
JournalPLoS pathogens
Volume10
Issue number4
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Sundqvist, E., Buck, D., Warnke, C., Albrecht, E., Gieger, C., Khademi, M., Lima Bomfim, I., Fogdell-Hahn, A., Link, J., Alfredsson, L., Søndergaard, H. B., Hillert, J., Barcellos, L., Booth, D., McCauley, J. L., Comabella, M., Compston, A., DAlfonso, S., De Jager, P., ... 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