Genetic Variation in OAS1 Is a Risk Factor for Initial Infection with West Nile Virus in Man

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Abstract
West Nile virus (WNV) is a re-emerging pathogen that can cause fatal encephalitis. In mice, susceptibility to WNV has been reported to result from a single point mutation in oas1b, which encodes 2′–5′ oligoadenylate synthetase 1b, a member of the type I interferon-regulated OAS gene family involved in viral RNA degradation. In man, the human ortholog of oas1b appears to be OAS1. The ‘A’ allele at SNP rs10774671 of OAS1 has previously been shown to alter splicing of OAS1 and to be associated with reduced OAS activity in PBMCs. Here we show that the frequency of this hypofunctional allele is increased in both symptomatic and asymptomatic WNV seroconverters (Caucasians from five US centers; total n = 501; OR = 1.6 [95% CI 1.2–2.0], P = 0.0002 in a recessive genetic model). We then directly tested the effect of this SNP on viral replication in a novel ex vivo model of WNV infection in primary human lymphoid tissue. Virus accumulation varied markedly among donors, and was highest for individuals homozygous for the ‘A’ allele (POAS1 SNP rs10774671 as a host genetic risk factor for initial infection with WNV in humans. When humans are exposed to infectious agents, the outcome may vary: some remain uninfected, some who become infected remain asymptomatic, and symptomatic individuals may develop clinical manifestations that vary in number and severity. Both host and environmental factors are thought to influence outcome. Here we show that a specific human mutation that results in reduced function in a known antiviral gene named OAS1 is associated with increased rate of infection with West Nile virus, a member of the flavivirus family. OAS1 codes for a component of the type I interferon signaling system; its homologue in mice has been shown previously to be important for flavivirus susceptibility. Individuals carrying two copies of the hypofunctional variant of OAS1 were found more frequently than expected among both asymptomatic and symptomatic WNV-positive individuals. To investigate further, we developed a novel model of WNV replication using human tonsil tissue in which high variability in replication was observed among donors. We found that the highest virus accumulation occurred in donors with two copies of the hypofunctional OAS1 variant. Together these data suggest that OAS1 activity may influence the probability of initial infection, but not the severity or symptomatic quality of infection, after WNV exposure in man.