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Testing a CCR5 drug? Avoid mosquito bites/West Nile Virus
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[NOTES AND QUOTES]
AIDS: Volume 20(8) 12 May 2006 p N3-N4
Crabb, Charlene
'Sleep under netting, wear long sleeves and pants, and use mosquito repellant', may be sage advice for HIV patients taking experimental CCR5-blocking drugs. Researchers at the National Institutes of Allergy and Infectious Diseases in Bethesda, Maryland, have discovered that the genetic mutation of the CCR5 surface protein that makes individuals highly resistant to HIV infection also leaves them more susceptible to potentially fatal infection of the mosquito-borne West Nile virus (WNV) (J Exp Med 2006; 203:35-40).
'The dilemma is that anti-HIV drugs now under development to block CCR5 are designed to imitate the effect of the natural mutation', explains Philip Murphy, who led the study. 'So they may be beneficial in HIV/AIDS but carry the cost of potentially increasing the risk of symptomatic West Nile virus infection in endemic areas'.
Since making its north American debut in New York City in 1999, WNV has spread to all 48 contiguous United States, southern Canada, Latin America and the Caribbean. The flavivirus, which primarily infects birds and mosquitoes, is now considered a seasonal north American epidemic that flares up in summer and continues through autumn.
Humans are mainly infected through mosquito bites. And although the majority of people never even know they have the virus, by conservative estimates approximately 1% of human infections result in severe illness, such as meningitis, encephalitis and paralysis, caused by the pathogen invading the brain. According to the US Centers for Disease Control and Prevention in Atlanta, 105 individuals died of WNV infection in the United States in 2005.
Last year, William Glass, a postdoctoral fellow in Murphy's laboratory discovered that when WNV infiltrates the brains of mice, immune system cells equipped with CCR5, the surface protein targeted by HIV, flood into the brain to battle the virus, allowing most mice to survive. However, when the researchers injected WNV into mice genetically engineered to make no CCR5, all the mice died of encephalitis within 12 days.
Interestingly, back in 1996, several research groups including Murphy's discovered CCR5_32, a defective allele for CCR5 that makes individuals highly resistant to HIV infection if both copies of the CCR5 gene are faulty. These homozygous individuals make none of the surface protein.
To see if such individuals are as vulnerable to WNV as the genetically engineered CCR5 knockout mice, Murphy's current team 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, respectively. Of these, 395 samples were suitable for genetic testing for the presence or absence of the HIV-protective mutation, which is found in approximately 1% of Caucasians in the United States.
The team's analyses showed that a significantly higher percentage of individuals with WNV infections had a pair of the faulty CCR5_32 alleles. In particular, 11 (4.5%) of the 247 WNV-positive samples from Arizona and six (4.1%) of the 148 WNV-positive samples from Colorado came from homozygous patients. In contrast, the mutation was found in only one (0.7%) of 145 individuals in Arizona who had WNV-like symptoms but did not have the viral infection. Among Coloradans who had a WNV infection and self-reported their race as Caucasian, six (8.3%) were homozygous for CCR5_32. (The increased frequency of the mutant genotype seen in WNV patients is similar in magnitude to that seen for individuals highly exposed to HIV who never become infected.)
The researchers concluded that in humans, as in mice, CCR5 is crucial to getting enough infection-fighting white blood cells into the brain to clear WNV and clean up the mess it has caused.
Murphy thinks the discovery is just 'the tip of the iceberg' of CCR5's usefulness. 'Up until now CCR5 has been a good-for-nothing gene', he says. 'It's been very famous for increasing the risk of HIV, but nobody really knew what it was good for. Now, finally, 10 years later, we've found something that it's good for. It protects the patient against West Nile virus infection. But, I think we're probably going to find that CCR5 is generally important for other causes of encephalitis.'
On the basis of the findings, the researchers note that participants in clinical trials for CCR5-blocking drugs should follow 'strict measures to limit mosquito exposure'. And their doctors should be alert to the occurrence of fever, headache, body aches, nausea, vomiting and other symptoms consistent with WNV infection.
Until recently, at least five CCR5-blocking drugs were in development. However, GlaxoSmithKline terminated clinical trials of aplaviroc last October because of cases of liver toxicity. Schering-Plough recently stopped phase IIb testing of vicriviroc in treatment-naive patients after the experimental drug failed to maintain low levels of HIV in several trial participants. The company will not begin phase III testing of the drug until completing a full evaluation of data from the phase II trials, which continue with treatment-experienced patients in the United States.
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