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Genetic factors increase risk of severe West Nile virus.

VAIL, COLO. -- The genetics of symptomatic West Nile infection has become a hot area of investigation with implications spilling over into clinical care.

Infection with West Nile virus (WNV) adheres to the typical arbovirus pyramid: Roughly 80% of human infections are entirely asymptomatic, 20% result in the nasty and debilitating febrile illness called West Nile fever, and about 1 in 150 infections lead to severe CNS disease. The question is, what's different about those 20% or so who develop symptomatic infections? Dr. Kenneth L. Tyler asked at a conference on pediatric infectious diseases sponsored by the Children's Hospital, Denver.

One factor may be the patients' age. In the 2002 Chicago-area outbreak, the incidence of WNV encephalitis was less than 5 cases per 100,000 among 45- to 59-year-olds, triple that in 60- to 74-year-olds, and more than the 30 per 100,000 among individuals aged 75 years and older, he said.

"Neurologic West Nile disease is relatively unheard of in infants, children, and young adults," observed Dr Tyler, professor of neurology, medicine, and microbiology at the University of Colorado Health Sciences Center, Denver.

A Centers for Disease Control and Prevention study comparing risk factors for development of WNV encephalitis versus West Nile fever in seropositive individuals showed that in addition to advanced age, other significant risk factors for encephalitis in a multivariate analysis were alcohol abuse, which conferred a 7.5-fold increased risk, and diabetes, with a 4.1-fold greater risk (Clin. Infect. Dis. 2006;42:1234-40).

There are also genetic factors involved. The first genetic risk factor to be identified for symptomatic WNV infection was a deletion mutation in the cell surface protein called chemokine receptor 5 (CCR5). In a meta-analysis involving 619 WNV-seropositive individuals, investigators at the National Institute of Allergy and Infectious Diseases demonstrated that homozygotes for the CCR5 delta 32 mutation had a fourfold increased risk of symptomatic disease (J. Infect. Dis. 2008;197:262-5).

CCR5 is important in guiding trafficking of inflammatory lymphocytes into the CNS, where they can help clear the WNV. Studies conducted in mouse models of WNV infection clearly demonstrate that in the presence of the delta 32 mutation, far fewer of these lymphocytes are present in brain tissue, reflecting inhibition of the cell-mediated host immune response to the viral pathogen, the neurologist explained.

In an unusual twist, more than a dozen years ago AIDS researchers discovered that CCR5 is the primary coreceptor used by HIV to infect cells. Homozygosity for CCR5 delta 32 was shown to confer powerful protection against HIV infection in exposed individuals. So the same mutation that protects an individual against acquiring HIV predisposes to neuroinvasive WNV disease, he said.

CCR5 antagonists, both monoclonal antibodies and small molecules, are a promising new class of investigational HIV drugs in active development, but it will be extremely important to protect patients on these drugs from bites by WNV-carrying mosquitoes.

Another genetic factor that affects WNV susceptibility is a single-nucleotide polymorphism in the gene encoding for oligoadenylate synthetase, which is part of the innate viral resistance defense system. Investigators at the Human Genome Sequencing Center at Baylor College of Medicine, Houston, found that the rs3213545 single nucleotide polymorphism was present in 84% of a group of patients with severe neurologic WNV disease but only 48% of seropositive individuals without severe disease (J. Infect. Dis. 2005;192:l,741-8).

Most recently, investigators at Washington University, St. Louis, have shown that Toll-like receptor 3 (TLR3), a viral sensor that's part of the innate immune system, protects against WNV infection in mice (J. Virol. 2008;82:10,349-58).

TLR3, when functioning normally, results in generation of high levels of inflammatory cytokines, including tumor necrosis factor--alpha and interleukin-6, in the periphery to help control WNV infection. But TLR3 expression is often reduced in the elderly, which may account for their increased propensity for severe WNV infection. The TLR3 findings provide a therapeutic rationale for studies of interferon alpha-n3 (Alfer-on) in the treatment of neurologic WNV disease, Dr. Tyler noted.
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Author:Jancin, Bruce
Publication:Internal Medicine News
Geographic Code:1USA
Date:Nov 1, 2009
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