Evidence that CCR5 is protective against West Nile virus: implications for CCR5 inhibitors

Much of the excitement around development of CCR5 inhibitors, despite set backs for two of the three current lead compounds in development, was related to the lack of evidence for a biological role for CCR5.

However, in a short article in the 12 May edition of AIDS [1], Charlene Crabb highlighted a recent paper in Journal of Experimental Medicine that linked CCR5 receptor usage to a protection against West Nile virus (WNV). [2]

WNV is a mosquito-borne virus that can infect birds, horses and other animals, and humans, and has spread across the US since 1999, where it is now considered endemic. Although 80% cases in the US of WNV remain subclinical, approximately 1% result in more serious illness including neuroinvasive disease, including meningitis, encephalitis which is often fatal, and/or flaccid paralysis.

After finding that WNV was fatal in mice with CCR5-delta32 deletion, William Glass and colleagues from NIAID then looked at whether this related to risk of human WNV infection. They found around 4% individuals in two cohorts of patients infected with symptomatic WNV were homozygous for CCR5 delta-32, compared to <1% of the general population. The magnitude of increased risk was statistically significant, with approximately 30% higher rates when looking at Caucasian patients only, and was linked to more severe progression of WNV irrespective of race (25-30% fatality vs <5% in overall population).

The authors concluded that this identified the first genetic susceptibility factor for WNV infection and also the first association of the CCR532 allele with susceptibility to an infectious disease. They cautioned that this may have implications for using CCR5 inhibitors in HIV-infected patients in areas endemic for WNV.

Comment

The proposed mechanism of action in mice is related to WNV inducing expression of CCR5 ligands in the WNV-infected mouse brain; and survival from WNV encephalitis though trafficking of leukocytes into the infected brain.

From 2001-2004 in the US, there were over16,500 laboratory confirmed cases of WNV reported to the CDC of which 648 were fatal (3.9%). [3]

Any risk from HIV-positive people using CCR5 inhibitors will be dependent on geographical risk of WNV which has not been reported in the UK. However, much of the interest generated by these findings, relates to identifying a role for CCR5, which may not now be as innocuous as was originally hoped.