CCR5 Deficiency Is a Risk Factor for Early Clinical Manifestations of West Nile Virus Infection but not for Viral Transmission

Abstract

Background West Nile virus (WNV) is a neurotropic flavivirus transmitted to humans by mosquito vectors. Homozygosity for CCR5Δ32, a complete loss-of-function mutation in the chemokine receptor CCR5, has been previously associated with severe symptomatic WNV infection in patients presenting with clinical disease, however whether it acts at the level of initial infection or in promoting clinical progression is unknown. Methods Here we address this gap in knowledge by comparing CCR5Δ32 distribution in US blood donors identified through a comprehensive blood supply screening program (n=34,766,863 donations from 2003–2008) as either WNV true positive (WNV+ cases; n=634) or false positive (WNV− controls; n=422). Results No difference was observed in CCR5Δ32 homozygous frequency between the WNV+ cases and WNV− controls, suggesting that CCR5 deficiency is not a risk factor for initial infection. However, CCR5Δ32 homozygosity was associated with worse clinical outcome, with these individuals developing more clinical symptoms as determined by a standardized questionnaire (P=0.0016). Conclusions Thus CCR5 deficiency is not a risk factor for WNV infection per se, but is a risk factor for both early and late clinical manifestations after infection. Our study also illustrates the power of large scale databases to answer important clinical questions in man.

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…This 32-basepair deletion in the CCR5 gene yields a truncated form of the protein, eliminating its surface expression. Lim et al [82] reported that CCR5Δ32 mutants were not associated with an increase in human susceptibility to WNV infection as had been observed in mice, but rather was present in individuals with an early clinical presentation of the disease and with higher frequencies of symptoms. Those individuals who were CCR5Δ32 homozygous had a higher frequency of multisystemic symptoms such as lymphadenopathy, neurological deficits and gastrointestinal complications.…”

“…CCR5 knockout (KO) mice display increased WNV titers in the CNS as well as a significant increase in mortality [52]. Subsequent human studies demonstrated an association between symptomatic WNV disease and a complete loss of CCR5 function through the acquisition of a mutation called CCR5Δ32 [81]. This 32-basepair deletion in the CCR5 gene yields a truncated form of the protein, eliminating its surface expression.…”

The role of chemokines in the pathogenesis of neurotropic flaviviruses

“…Several epidemiologic studies have been conducted to evaluate the role of CCR5 in controlling WNV infection in humans as well [26,27,[38][39][40]. These studies have analyzed the complete loss-of-function allele, CCR5D32, among WNV-infected cohorts.…”

Association between RANTES -403A/G polymorphism and susceptibility to hepatitis B virus infection: A meta-analysis

“…The RANTES-CCR5 pathway have shed some light on viral clearance mechanisms, such as with hepatitis C virus [28,29] and West Nile virus [30]. Studies have demonstrated that it plays an important role in sustaining CD8 T cell responses during the chronic infection [31,32].…”