A genetic mutation that protects against HIV increases the risk of developing clinical West Nile Virus infection, according to a new study appearing online on January 9th in The Journal of Experimental Medicine.
The mutation in question is a small deletion in a gene that encodes a protein called CCR5, which was identified in 1996 as a co-receptor used by HIV to infect cells. Individuals with two copies of this mutation (CCR5delta32) 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, for the treatment of patients with HIV. CCR5 seemed like an ideal drug target, as people missing the receptor were healthy and no diseases or infections had been shown to be more frequent or severe in individuals carrying the CCR5delta32 mutation.
But new evidence suggests that the lack of CCR5 is not completely innocuous. Philip Murphy and his colleagues at the National Institute of Allergy and Infectious Diseases (Bethesda, MD) recently showed that infection with WNV -- a mosquito-borne virus that caused a1999 outbreak of fatal encephalitis in the US -- was uniformly fatal in mice that lack CCR5.
This finding prompted Murphy and his colleagues to look for the CCR5delta32 mutation in patients in the US who were diagnosed with WNV infections. They now report that individuals with two copies of CCR5delta32 were more frequent among WNV patients than in the general population, suggesting that the lack of CCR5 puts people at risk for developing clinical WNV infections. In mice, the lack of CCR5 prevents protective immune cells from gaining access to the brain where they can fight off the infection. It remains to be seen whether the same mechanism is at play in humans.
This study might 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.
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