"This is the first genetic risk factor to be identified for West Nile virus infection," says NIH Director Elias A. Zerhouni, M.D. "While infection does not always lead to illness, the virus can sometimes cause serious problems and, according to the Centers for Disease Control and Prevention, there were 102 deaths in the United States from West Nile virus infection in 2005."
"A decade ago, a number of research groups, including Dr. Murphy's, determined that CCR5 is the primary co-receptor used by HIV to infect cells," says NIAID Director Anthony S. Fauci, M.D. "Their work laid the foundation for the development of CCR5-blocking drugs, which are designed to slow the spread of HIV from cell to cell."
Most people inherit two normal copies (one from each parent) of the gene that codes for CCR5 protein. About 1 percent of North American whites, however, have a mutation in both copies (are homozygous) and thus do not produce any CCR5. These individuals have the good fortune of being highly resistant to HIV infection and otherwise seemed to suffer no ill effects from the absence of this receptor protein, scientists noted. But the new research by Dr. Murphy's team suggests that lacking CCR5 may not be an unalloyed good after all.
In 2005 Dr. Murphy and his coworkers developed a mouse model to clarify the roles of various immune system cells in responding to WNV infection. They discovered that while most mice survived WNV infection, mice genetically engineered to lack CCR5 receptors suffered rapid and uniformly fatal infection by the virus. Further investigation showed that CCR5 promoted the movement of several classes of immune system cells into the brain and central nervous system, which appeared to protect normal mice from the encephalitis (brain inflammation) characteristic of serious WNV infection.
"We wanted to know if humans lacking CCR5 might be at greater risk of the more serious complications of WNV infection," says Dr. Murphy. The researchers examined human blood and cerebrospinal fluid samples from 417 laboratory-confirmed cases of WNV infection that occurred in Arizona and Colorado in 2003 and 2004. Of these, 395 were suitable for genetic testing for the presence or absence of the HIV-protective mutation.
Dr. Murphy and his colleagues determined that 4.5 percent of 247 WNV-positive samples from Arizona were from patients who had two copies of the CCR5 mutation. In contrast, a control group of 145 WNV-negative blood samples showed 0.7 percent were from people who had two copies of the CCR5 mutation--a number in line with the expected 0.8 to 1 percent range believed to be present in all North American whites. Next, the researchers analyzed the WNV-positive samples from Colorado and determined that 4.1 percent of the entire set of 148 samples came from individuals homozygous for the CCR5 mutation. Among those Coloradans who provided WNV-positive samples and who self-reported their race as white, the percentage of homozygous individuals was 8.3.
The absence of normal CCR5 genes is a strong genetic risk factor for developing symptomatic cases of WNV infection, the researchers conclude. "The findings may have important clinical implications for physicians who treat people with HIV," notes Dr. Murphy. For example, he says, it may be prudent for HIV-positive individuals who are taking experimental CCR5-blockers to strictly limit mosquito exposure.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
References: WG Glass et al. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. The Journal of Experimental Medicine 202:1087-98 (2005). DOI: 10.1084/jem.20042530.
WG Glass et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. The Journal of Experimental Medicine. (Published online Jan. 17, 2006) DOI: 10.1084/jem.20051970.
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