People who lack a cell surface protein called CCR5 are highly resistant to infection by HIV but may be at increased risk of developing West Nile virus (WNV) illness when exposed to the mosquito-borne virus, report researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The findings may have cautionary implications for physicians who are treating HIV-positive individuals with experimental CCR5-blocking drugs, say the scientists.

"This is the first genetic risk factor to be identified for West Nile virus infection. While infection does not always lead to illness, the virus can some times cause serious problems and, according to the Centres for Disease Control and Prevention, there were 102 deaths in the United States from West Nile virus infection in 2005," said NIH Director Elias A. Zerhouni.

"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. 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," said NIAID Director Anthony S. Fauci.

Most people inherit two normal copies (one from each parent) of the gene that codes for CCR5 protein. About 1 per cent 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 co-workers developed a mouse model to clarify the roles of various immune system cells in responding to WNV infection. They discovered that while most wild-type 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," said 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 per cent 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 per cent were from people who had two copies of the CCR5 mutation, a number in line with the expected 0.8 to 1 per cent range believed to be present in all North American whites. Next, the researchers analysed the WNV-positive samples from Colorado and determined that 4.1 per cent of the entire set of 148 samples came from individuals homozygous for the CCR5 mutation. Among those Coloradoans 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. For example, it may be prudent for HIV-positive individuals who are taking experimental CCR5-blockers to strictly limit mosquito exposure," said Dr. Murphy.