Unintended side effect of blocking CCR5...
jem.org
Published online January 17, 2006 doi:10.1084/jem.20051970
© Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 35-40
CCR5 deficiency increases risk of symptomatic West Nile virus infection
William G. Glass1, David H. McDermott1, Jean K. Lim1, Sudkamon Lekhong2, Shuk Fong Yu2, William A. Frank3, John Pape4, Ronald C. Cheshier2, and Philip M. Murphy1
1 Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
2 Bureau of State Laboratory Services and 3 Bureau of Epidemiology and Disease Control Services, Arizona Department of Health Services, Phoenix, AZ 85007
4 Colorado Department of Public Health and Environment, Denver, CO 80246
CORRESPONDENCE Philip M. Murphy: pmm@nih.gov
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 CCR532, 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 CCR532 in a control population of healthy United States Caucasian random blood donors was in Hardy-Weinberg equilibrium and CCR532 homozygotes represented 1.0% of the total group (n = 1,318). In contrast, CCR532 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). CCR532 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.
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W.G. Glass's present address is Centocor Global R&D, Infectious Diseases, Radnor, PA 19087.
Related Article
CCR5 thwarts West Nile virus
Heather L. Van Epps
J. Exp. Med. 2006 203: 4. [Full Text]
jem.org
Published online January 17, 2006 doi:10.1084/jem2031iti6
© Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 4-4
CCR5 thwarts West Nile virus
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Individuals homozygous for the CCR532 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 (CCR532) 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 CCR532. 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 CCR532 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 CCR532 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 CCR532 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.
Heather L. Van Epps
hvanepps@rockefeller.edu |
