Mutated gene can delay onset of AIDS.

For years scientists have wondered why some HIV-positive people develop AIDS promptly, while others seem to ward off the disease indefinitely.

Researchers know that a mutation in a gene called CCR5 renders roughly 1 percent of white people highly resistant to HIV infection. Such people receive the mutant gene from both parents. Individuals who inherit the CCR5 mutation from just one parent can contract HIV, but the onset of AIDS is delayed 2 to 4 years.

Now, in a genetic deja vu, researchers have found a mutation in a second gene, called CCR2--this one carried by up to one-fourth of all people-that also seems to postpone the onset of AIDS in HIV-positive individuals by 2 to 4 years. The gene does not prevent infection, however.

The CCR2 gene sits next to its cousin CCR5 on chromosome 3. Both genes encode proteins called chemokine receptors, which act as docking stations on the outer surface of immune cells.

When cells are damaged, they produce chemokines, proteins that attract immune cells. To hijack these immune cells, HIV latches onto their chemokine receptors, preventing the chemokines from docking. The CCR5 mutation results in a shortened receptor, thus thwarting HIV's ability to take over the immune cells (SN: 8/17/96, p. 103).

Discovery of the CCR5 mutation last year spawned a flurry of research to identify other genes that encode chemokine receptors. The new study, led by researchers at the National Cancer Institute in Frederick, Md., indicates that HIV may also need normal CCR2 chemokine receptors to progress rapidly to AIDS. Defective CCR2 receptors, which appear in about 20 to 25 percent of people of all races, are probably difficult for the virus to commandeer. The prevalence of such faulty receptors may explain, in part, the wide variation in survival rates of HIV-positive people.

The researchers studied 3,003 blood samples from people at risk of getting HIV. Most were found to be HIV-positive. Roughly half of the HIV-positive individuals who survived more than 16 years have either the CCR2 or CCR5 mutation, the researchers report in the Aug. 15 Science.

The findings raise tantalizing possibilities. "if we could mimic the effects of these mutations, either by designing a drug or by gene therapy, then you would have the hope of delaying AIDS onset for a long period, if not indefinitely," says study coauthor Stephen J. O'Brien, who heads NCI's genomic diversity laboratory.

The NCI researchers don't know how the altered CCR2 receptor delays AIDS. The CCR5 receptor is used by the most prevalent HIV strains, while the CCR2 receptor is rarely used by viruses, says Robert W. Doms, a pathologist at the University of Pennsylvania in Philadelphia. "There might be some other mutation that we still haven't found yet," he says. Nevertheless, the study sheds needed light on the biology of chemokine receptors, he adds.

"They are the linchpins for HIV," says Dan R. Littman, an immunologist and Howard Hughes Medical Institute investigator at New York University. However, Littman doubts that the CCR2 receptor itself plays a major role. He suggests that it may regulate CCR5 receptor proteins in some way, possibly tipping the chemokine balance in the process and discouraging the virus from locking onto a cell.

Much is left to study, and the terrain is still new.

"It is striking to recall that a family of proteins as large and ubiquitously expressed as chemokines and their receptors was unknown less than 10 years ago," writes Barrett J. Rollins of the Dana-Farber Cancer Institute in Boston in the Aug. 1 Blood.