CCR5 Deficiency/Susceptibility to Symptomatic CNS Infection with Flaviviruses
CCR5 Deficiency/Susceptibility to Symptomatic CNS Infection with Flaviviruses
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.
Synopsis: Homozygosity for a 32 base pair deletion in CCR5 (CCRDD32) is associated with an increased risk of symptomatic infection with two flaviviruses.
Sources: Lim JK, et al. Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic. J Infect Dis 2008; 197: 262-5; Kindberg E, et al. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tick-borne encephalitis. J Infect Dis. 2008;197:266-269.
It was recently reported that the prevalence of homozygosity for CCR5 delta 32, a nonfunctional variant of the chemokine receptor CCR5, is markedly increased among symptomatic WNV-seropositive patients from Arizona and Colorado.1 The paper by Lim et al summarized above analyzed additional cohorts from California and Illinois. A meta-analysis performed on the combined dataset showed an OR of 4.2, demonstrating that CCR5 deficiency is a strong risk factor for symptomatic WNV infection in the United States. The second paper from Scandinavia and the Baltic region showed a similar association between CCR5 delta 32 and symptomatic infection with another flavivirus, TBE.
Commentary
It has been almost 12 years since the chemokine receptors CCR5 and CXCR4 were identified as the major coreceptors for HIV.2 It was subsequently recognized that homozygosity for CCR5D32 rendered humans virtually immune to de novo infection by HIV, and that heterozygosity for this deletion, while allowing HIV infection, generally resulted in long term non-progressive infection.3,4 Just within the last year, the first small molecule inhibitor of CCR5 (maraviroc) was granted marketing clearance by the US FDA for treatment of HIV infection. Individuals who are homozygous or heterozygous for this CCR5 delta 32 mutation generally appear to be immunologically normal, and no clinically apparent adverse effects on the immune system have been seen with clinical use of maraviroc or other chemokine receptor antagonists currently in development. This is probably a reflection of the redundancy of the human immune system and the overlapping nature of the chemokine cascade. The two studies described above show that the carriage of the CCR5D32 allele is a risk factor for severe infection with the flaviviruses, WNV, and TBE. While neither of these studies explores the mechanisms which mediate this effect, the results raise numerous questions, the answers to which will undoubtedly expand our understanding of the pathogenesis of neuroinvasive viral infections.
References
- Glass WG, et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med. 2006;203:1087-1098.
- Deng H, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996;381:661-666.
- Samson M, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene. Nature. 1996;382:722-725.
- Liu R, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86:367-377.
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