CCR5 deficiency increases risk of symptomatic West Nile virus infection

William G Glass, David H McDermott, Jean K Lim, Sudkamon Lekhong, Shuk Fong Yu, William A Frank, John Pape, Ronald C Cheshier, Philip M Murphy, William G Glass, David H McDermott, Jean K Lim, Sudkamon Lekhong, Shuk Fong Yu, William A Frank, John Pape, Ronald C Cheshier, Philip M Murphy

Abstract

West Nile virus (WNV) is a reemerging pathogen that causes fatal encephalitis in several species, including mouse and human. Recently, we showed that the chemokine receptor CCR5 is critical for survival of mice infected with WNV, acting at the level of leukocyte trafficking to the brain. To test whether this receptor is also protective in man, we determined the frequency of CCR5Delta32, a defective CCR5 allele found predominantly in Caucasians, in two independent cohorts of patients, one from Arizona and the other from Colorado, who had laboratory-confirmed, symptomatic WNV infection. The distribution of CCR5Delta32 in a control population of healthy United States Caucasian random blood donors was in Hardy-Weinberg equilibrium and CCR5Delta32 homozygotes represented 1.0% of the total group (n = 1,318). In contrast, CCR5Delta32 homozygotes represented 4.2% of Caucasians in the Arizona cohort (odds ratios [OR] = 4.4 [95% confidence interval [CI], 1.6-11.8], P = 0.0013) and 8.3% of Caucasians in the Colorado cohort (OR = 9.1 [95% CI, 3.4-24.8], P < 0.0001). CCR5Delta32 homozygosity was significantly associated with fatal outcome in the Arizona cohort (OR = 13.2 [95% CI, 1.9-89.9], P = 0.03). We conclude that CCR5 mediates resistance to symptomatic WNV infection. Because CCR5 is also the major HIV coreceptor, these findings have important implications for the safety of CCR5-blocking agents under development for HIV/AIDS.

Figures

Figure 1.
Figure 1.
CCR5 deficiency is associated with increased risk of death from WNV infection. Data presented are from the Arizona WNV-seropositive cohort and demonstrate that CCR5Δ32 homozygosity is associated with fatal outcome in both the race-unstratified (OR = 8.5 [95% CI, 1.5–48.2], P = 0.04) and self-reporting Caucasian (OR = 13.2 [95% CI, 1.9–89.9], P = 0.03) groups.

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