Association between HLA Class I and Class II Alleles and the Outcome of West Nile Virus Infection: An Exploratory Study

Abstract

BackgroundWest Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease.MethodsA cohort of 210 non-Hispanic mostly white WNV+ subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome.ResultsThe alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, P A*68 = 0.013/Pc = 0.26, P C*08 = 0.0075/Pc = 0.064, and P DQB1*05 = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, P B*40 = 0.021/Pc = 0.58 and AS vs. ND P C*03 = 0.039/Pc = 0.64) and their frequencies were lower within WNV+ subjects with neuroinvasive disease than within the North American population (NA vs. S, P B*40 = 0.029 and NA vs. ND, P C*03 = 0.032).ConclusionsHost HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as “susceptible” alleles, whereas HLA-B*40 and C*03 might function as “protective” alleles.

Virus Antibody Survey in Different European Populations Indicates Risk Association Between Coxsackievirus B1 and Type 1 Diabetes

“…Previous studies suggested that these genotypes may modulate antibody responses against EVs (20) and detection of EVs in patients with type 1 diabetes (21). The HLA genotype is also known to modulate the immune response and the course of many other viral infections (22,23). However, such an HLA effect can hardly explain the elevated CVB1 antibodies in patients with type 1 diabetes because the risk effect of CVB1 remained when adjusted for the effect of HLA, and it was seen in Finland where case and control subjects were matched for diabetes-associated HLA genotypes.…”

West Nile Virus: Biology, Transmission, and Human Infection

“…Certain HLA types appear to be associated with risk of a more severe outcome (HLA-A*68 and C*08) or better resistance to infection (B*40 and C*03) (107). Single nucleotide polymorphism (SNP) studies have detected SNPs in key regulators of immune function, including interferon pathway elements.…”

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…The OAS gene cluster activates an important mediator of viral RNA degradation, RNAse L. In humans, sequencing of the OAS gene cluster in 33 individuals with severe WNV infections did not reveal deletions or nonsense mutations; however, 23 single nucleotide polymorphisms (SNPs) in OAS genes were identified that occurred at a higher frequency in symptomatic individuals. In another study, an allele of OAS1 ('A' allele at SNP rs10774671) that enhanced mRNA splicing was more common in WNV-infected individuals than in uninfected controls [76]. That study also tested the function of the SNP on viral replication in an ex vivo model using primary human lymphoid tissue and determined that virus replication varied among the donors and was most efficient among individuals who were homozygous for the 'A' allele [80].…”