Published online 16 July 2008 | Nature | doi:10.1038/news.2008.948

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African mutation may increase HIV infection

Genetic quirk fends off malaria, but may render Africans more vulnerable to HIV.

A genetic mutation that allows African people to resist a form of malaria may also leave them more prone to HIV infection, according to a genetic survey of 3,400 people. But paradoxically, once infected with HIV, those who had the mutation lived on average 2 years longer than those without it.

The mutation results in the loss of a protein found on red blood cells. The protein, called DARC (Duffy antigen receptor for chemokines), binds to immune-system proteins called chemokines that can trigger inflammation.

Clinic patientA genetic mutation that confers resistance to malaria may leave some Africans more prone to HIV infectionWHO

Two malaria parasites, Plasmodium vivax and Plasmodium knowlesi, use the DARC protein to invade blood cells. People who lack DARC are resistant to these particular parasites, but not to other malaria-causing pests such as the more deadly Plasmodium falciparum.

Nearly all Africans carry a mutation near the DARC gene that prevents its expression. "It's a tradeoff," says Robin Weiss, an HIV researcher at University College London and part of the team that has found the new HIV link. "This genetic factor that has made sub-Saharan Africans resistant to vivax malaria is also making them more susceptible to HIV."

Outside influences

In recent years, researchers have compiled a growing list of human genes that may influence HIV infection. A mutation in another protein that interacts with chemokines, called CCR5, reduces infection rates and is found in about 1% of Caucasians in North America. Several drug companies are developing anti-HIV therapies that target the CCR5 protein. And last year, a genome-wide survey revealed several genes that are linked to the severity of HIV infection and disease progression1.

Such studies can reveal new pathways used by the virus during infection, and may also help to explain why some populations are more vulnerable to HIV than others, says Cheryl Winkler, who studies the genetics of infectious diseases at the US National Cancer Institute in Maryland. Although the AIDS epidemic has ravaged Africa, no one had found a genetic risk factor that is specific to the African population.

Previous work had shown that DARC could help HIV bind to red blood cells2, and Weiss and his colleagues decided to test DARC’s role in HIV infection. They confirmed that HIV attaches to red blood cells using DARC, and then surveyed around 3,400 African Americans to ascertain the mutation’s effect on HIV infection. The researchers surveyed African Americans rather than Africans because the DARC mutation is so common in Africa that there would have been few Africans without the mutation to serve as a comparison.

African Americans who carried the mutation were 40% more likely to be infected with HIV. The study, published in Cell Host and Microbe,3 must be repeated before researchers can be certain, but the current results suggest that as much as 11% of the HIV-1 infections in Africa may exist because of the mutation. "If it’s true, it would have a huge impact," says Winkler.

Unanswered questions

The results add to the evidence that chemokines may be important during HIV infection, but no one knows exactly how the absence of the DARC receptor encourages the virus. One possibility, says Sarah Rowland-Jones of the Medical Research Council Laboratories in Banjul, The Gambia, is that the DARC protein contributes to an important immune response.

The researchers also found that those who lack DARC and become infected with HIV live slightly longer than HIV-infected individuals who have DARC. The reasons for that remain unclear, says Weiss. "It’s counterintuitive," he says, noting that most other risk factors that enhance HIV infection are also associated with faster development of the disease.

An important next step will be to repeat the experiment using another group of patients, says Winkler, to ease concerns that the association found by Weiss and his colleagues is not a coincidence. The subjects in the study were all members of the military, and that implies a certain degree of social and economic equality. But further studies are needed to address the possibility that other factors could have played a role in generating the association Weiss and his colleagues found, she says.

"It is a provocative paper that will stimulate research in the field," says Winkler. "But I don’t believe this is a done deal." 

  • References

    1. Fellay, J. et al. Science 317, 944-947 (2007). | Article | PubMed | ISI | ChemPort |
    2. Lachgar, A. et al. Biomed. Pharmacother. 52, 436-439 (1998). | Article | PubMed | ChemPort |
    3. He, W. et al. Cell Host Microbe 4, 52-62 (2008). | PubMed |
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