Health

Variation in two key genes can predict the course of an HIV-infected patient's progression to AIDS, according to a new study.

Until now, viral load - the concentration of the HIV virus in the blood - was thought to be the major predictor of how a person will fare against AIDS. But the new research suggests that cell-mediated immunity - the way key immune cells respond to infection - may be almost as important.

Also, the combination of two key genes involved in cell-mediated immunity may help predict the course of infection, suggests the study led by Sunil Ahuja, at the University of Texas, and Matthew Dolan at the Wilford Hall United States Air Force Medical Center, both in San Antonio, US.

HIV has been found to attack "helper" T-cells, also known as CD4 cells, which help coordinate immune responses in the body. The CD4 count declines as a result, leading to infection from other illnesses, and very often death. But how quickly the progression occurs varies enormously, and about 10% of people with HIV don't develop this vulnerability to infection.

That suggests that there is something about the host person that influences how the disease plays out, say Ahuja and Dolan.

Gene combination

They showed in a paper in Science (vol 307, no 5714, p 1434) two years ago that the number of copies of the CCL3L1 gene, which codes for an immune messenger called a chemokine, was a major determinant of a person's risk of acquiring HIV and progressing rapidly to AIDS. The more copies of the gene a person had, the more resistant they were. At the time, it was thought that resistance was entirely to do with the gene's effect on viral load.

Now the team has studied 3500 HIV-infected and healthy people. They examined CCL3L1 plus a gene for a chemokine receptor, CCR5.

They found that a specific combination of one or no CCL3L1 gene plus a particular variant of CCR5, was associated with very poor cell-mediated immunity, as demonstrated through a simple skin-reactivity test. The two genes also predicted how the disease would progress in a subset of patients with AIDS.

'Uneven race'

"It's not an even race," says Dolan. "Some will do well and some will do poorly. And some of that is preordained before people get infected."

The researchers calculate that about 6% of the variability in disease progression between individuals comes from this gene combination's influence on cell-mediated immunity. The finding is important because only 9% of variability can be explained by measures of viral load - considered to be best predictor at present for how the disease will progress. It is not just the viral burden itself that matters, they argue, but the interplay between the virus and the host.

"They have intrigued everyone," says Mary Carrington, at the National Institutes of Health in Bethesda, Maryland, US. But now it's time to try to understand the biology, she says, "rather than simply looking at the copy number".

Journal reference: Nature Immunology, (DOI: 10.1038/ni1521)

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