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.

Immunology of progressive multifocal leukoencephalopathy

“…However, JCV viremia was observed in patients that were seronegative for anti-JCV VP1 antibodies, indicating that testing JCV-specific antibodies might not be sufficient to stratify the risk for some natalizumab-treated MS patients (Major et al, 2013). Interestingly, serum JCV VP1-specific antibody levels are increased in patients at onset of natalizumab-associated PML compared to natalizumab-treated MS patients (Trampe et al, 2012;Warnke et al, 2013;Warnke et al, 2014). PML survivors in the context of AIDS show significant increases in JCV-specific T cells and IgG responses in the peripheral blood, which are positively correlated with peripheral CD4 + T cell counts (Khanna et al, 2009).…”

“…PML survivors in the context of AIDS show significant increases in JCV-specific T cells and IgG responses in the peripheral blood, which are positively correlated with peripheral CD4 + T cell counts (Khanna et al, 2009). PML patients show generally JCV-specific oligoclonal IgG bands in the CSF and elevated intrathecal JCV VP1-specific antibodies with further increase at onset of IRIS (Aly et al, 2011;Sindic et al, 1997;Warnke et al, 2014;Weber et al, 1997). This goes in line with the observation that plasma cells are prominent -4-among the brain immune infiltrates in PML-IRIS (Aly et al, 2011;Metz et al, 2012).…”

Immunological biomarkers identifying natalizumab-treated multiple sclerosis patients at risk of progressive multifocal leukoencephalopathy

“…By determining HLA-alleles with single-nucleotide polymorphism imputation, PCR amplification with sequence-specific primer kits, or with a reverse PCR sequence-specific oligonucleotide method, a strong association between class II gene variants and JCV infection was found in Scandinavian and German patients with MS and in Swedish controls (Sundqvist et al, 2014). In particular, alleles within the HLA-DRB1*15 haplotype appear to be associated with a protective effect on JCV infection, while alleles within the DQB1*06:03 haplotype provide an opposite association.…”

“…JCV infection control involves the recognition of viral antigens by CD4 + lymphocytes carrying the "appropriate" HLA-class II molecules (Sundqvist et al, 2014), and the subsequent activation of cytotoxic CD8 + T cells. These activities are accompanied by phenotypic and functional modifications that require an enhanced supply of ATPgenerating metabolites to meet the increased bioenergetic demands (Fox et al, 2005).…”

Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant

“…14,15 However, the frequent -4-occurrence of PML during HIV infection, its occurrence in idiopathic CD4 + lymphopenia, the association of HLA class II alleles with JCV-specific T cell responses and the analysis of brain-infiltrating T cells in PML-IRIS all suggest that CD4 + T cells also play an important role in controlling JCV infection. [16][17][18][19][20][21] Our analysis of brain-infiltrating lymphocytes in natalizumab-associated PML-IRIS demonstrated highly abundant and clonally expanded JCV VP1-specific CD4 + T cells, which deploy a broad spectrum of different strategies to mount an efficient JCV-specific immune response. 16,17 Here, we report that JC viral persistence in the CNS may occur even after immune reconstitution and despite intrathecal JCV-specific T cell and antibody responses.…”