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

• Published in: PLoS pathogens Vol. 10; no. 4; p. e1004084
• Main Authors: 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, Oturai, Annette B., Hemme, Bernhard, Kockum, Ingrid, Olsson, Tomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: Alleles; Antigens; Biology and Life Sciences; Brain research; CD4-Positive T-Lymphocytes - immunology; Colleges & universities; Disease; Epidemiology; Female; Genetic aspects; Genetic research; Genetic variation; Genetics; Haplotypes; Health aspects; HLA-DQ beta-Chains - genetics; HLA-DQ beta-Chains - immunology; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; Hospitals; Host-parasite relationships; Humans; Immune system; Infections; JC Virus; Leukocytes; Male; Medicine; Medicine and Health Sciences; Microbiological research; Multiple sclerosis; Neurology; Neurosciences; Polyoma virus; Polyomavirus Infections - genetics; Polyomavirus Infections - immunology; Scandinavian and Nordic Countries; Scandinavian and Nordic Countries; Germany
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004084

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.