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Individuals homozygous for the CCR5Δ32 allele are more likely to suffer from fatal West Nile Virus infection.

A genetic mutation that protects against HIV infection increases the risk of developing clinical West Nile virus (WNV) infection, according to Glass and colleagues on page 35.

The mutation in question is a 32-bp deletion in a gene that encodes the chemokine receptor CCR5, which was identified in 1996 as a cellular coreceptor for HIV. Individuals homozygous for this mutation (CCR5Δ32) are highly resistant to HIV infection, even when repeatedly exposed to the virus. This resistance was the theoretical basis for the development of therapeutic CCR5 inhibitors, several of which are now in clinical trials. CCR5 seemed like an ideal drug target, as people missing the receptor were healthy and no diseases or infections were known to be more frequent or severe in individuals homozygous for CCR5Δ32. Mice appeared to be equally unfazed by the lack of CCR5.

But new evidence suggests that the lack of CCR5 is not completely innocuous. This group recently showed that infection with WNV—a mosquito-borne virus that has spread rapidly across the United States since 1999, often causing fatal encephalitis—was uniformly fatal in mice lacking CCR5. This finding prompted the group to look for the CCR5Δ32 allele in two cohorts of patients in the United States who had symptomatic WNV infections. They now report that 4–5% of the infected individuals were homozygous for the CCR5Δ32 allele, compared with less than 1% of the general population, suggesting that the lack of CCR5 puts people at risk for developing clinical WNV infections. The magnitude of this risk is comparable to the magnitude of protection against HIV that is conferred by this genotype. It remains to be tested whether CCR5-deficient humans, like mice, develop more severe disease because fewer protective immune cells gain access to the brain.

This study identifies not only the first genetic susceptibility factor for WNV infection but also the first association of the CCR5Δ32 allele with susceptibility to an infectious disease. These data might also raise a red flag for the use of CCR5 inhibitors in HIV-infected patients—at least in areas endemic for WNV—as such inhibitors might increase the recipients' vulnerability to severe WNV infection.