As long as HIV and AIDS have existed, there has been a small minority who have contracted the virus, but not the disease. Their bodies are somehow able to control HIV, making them less contagious and immune to AIDS symptoms, sometimes forever. A new genomic study of nearly 1,000 of these people, known as “HIV controllers,” has found the genetic reason behind this.

The researchers examined the DNA of 974 controllers and, by performing a genome-wide association analysis, compared it with DNA from 2,648 patients whose disease has progressed.

“Of the three billion nucleotides in the human genome, it really comes down to just a handful that relate to a particular function of the immune system that makes the difference,” says Bruce Walker, a virologist at Massachusetts General Hospital, and one of the two lead researchers on the study, published online today by the journal Science.

These nucleotides, or pieces of genetic material, are located at a genomic region that encodes proteins needed for immunity—an obvious spot that had been considered before by researchers. But because virtually all of the differences found between HIV controllers and those whose disease had progressed were in this area, scientists can now better target their research.

“There have been lots of theories that these controllers might be manifestations of multiple mechanisms,” says Warner Greene, director of the Gladstone Institute of Virology and Immunology at the University of California, San Francisco, who was not involved in the research. “This tends to focus the field.”

The study identified differences in a region of chromosome 6, where there are genes that control a key part of the immune system called the human leukocyte antigen, which is a molecule on the surface of a cell. When that molecule holds a bit of a virus, it’s a signal to other cells that the cell is infected and needs to be destroyed. Depending on the amino acids present in the molecule, the part of a virus that is held will be slightly different, and that’s what makes the difference for someone who is an HIV controller.

It’s much too early, Walker and Greene both say, to use this information to design a drug or vaccine for HIV, but it is a step in that direction.

“I think this gives us really important insights into the type of reactions that occur during the immune response that lead to high-level control of HIV,” Greene says. “If we had a vaccine that would make everybody a controller—that would be spectacular.”

Roughly one in 300 people who test positive for HIV are controllers, Walker says. The immune systems of these people maintain fewer than 2,000 RNA copies of the virus per milliliter of blood plasma. Most people with HIV carry a viral load of hundreds of thousands to five million copies per milliliter, depending on the stage of infection.

The study’s other lead author, Paul de Bakker, an assistant professor at Brigham & Woman’s Hospital and an associate member of the Broad Institute, says he next wants to look for rare gene variants that might also help explain why some people’s immune systems are better able to control HIV.