San Francisco Chronicle - The Voice of the West, 901 Mission Street, San Francisco, CA 94119 - Friday, September 27, 1996 - Page A1
David Perlman, Chronicle Science Editor

And after undertaking genetic tests of nearly 2,000 people at high risk for the disease, the researchers have also found that men who inherit only one of the naturally altered genes can fall prey to the infection but develop the disease much more slowly and live significantly longer than most AIDS patients.

The first intriguing clues to the protective role of the altered genes were reported only three months ago, based on gene studies in a small number of men. Since then, scientists have predicted that because the clues add powerful insights into the processes that lead to AIDS, the discoveries should yield new approaches to AIDS drug and vaccine development.

The report, published today in the journal Science, comes from research teams at the National Cancer Institute's laboratories in Bethesda and Frederick, Md., and from six large-scale epidemiological studies.

Leaders of those studies have followed men known as "long- term non-progressors" because these subjects have not developed the disease for a dozen years or more after being infected by the human immunodeficiency virus, or who have remained free of infection despite years of unsafe sex.

In one study, Dr. Susan Buchbinder of the San Francisco health department has tracked 600 men for more than a dozen years.

Two hundred of those men who are among the "non-progressors" apparently inherited a single copy of the defective gene, she said yesterday. And three others who inherited copies of the defective gene from both parents have remained free from infection despite years of high-risk unprotected sex with many male partners, Buchbinder said.

Despite the provocative findings of the national study, Buchbinder cautioned yesterday that there may well be other undiscovered genetic factors that can contribute to resistance against HIV's invasion of the immune system. Men who remain uninfected for a while after unsafe sex should by no means believe that they are genetically immune, she said.

"The new evidence from the large-scale study is somewhat suggestive," Buchbinder said, "but it's by no means conclusive."

The defective gene under study is called CKR-5. It carries the genetic code for one of at least three proteins in a class of molecules called chemokines. Scientists have long known that to infect humans, the AIDS virus must lock onto a protein called the CD-4 receptor, located on the outer membranes of immune system cells. But they have also believed that other molecules known as co-factors must be involved in the infection process.

Now it appears that the newly discovered CKR-5 chemokine is a long-sought co-factor needed for HIV to launch its potentially lethal invasion of the immune system's protective cells, and that alterations in the gene that determine its structure can block the virus or at least slow its ability to reproduce swiftly and cause disease.

The principal researchers reporting on the study today include Stephen J. O'Brien, Michael Dean and Mary Carrington of the National Cancer Institute, plus leaders of AIDS studies in Los Angeles, Baltimore, Pittsburgh, Boston and Birmingham, Ala., as well as San Francisco.

The scientists tracked 1,955 people who were at risk of AIDS, including hundreds of sexually active gay men, intravenous drug users and hemophiliacs who had received virus-contaminated blood- clotting transfusions years ago.

Records and blood samples from the entire group had been followed for eight to 18 years, and genetic tests of their frozen blood showed that of 282 people who had a single altered copy of the CKR-5 gene, 195 had been infected with HIV. But the infected members of that group had either progressed far more slowly to disease than most AIDS patients or -- among those who had already died -- had lived an average of three years longer than most AIDS patients do.

The researchers said they also found 17 men who had inherited two copies of the altered gene and who had remained uninfected despite repeated exposure to the virus.

According to the geneticists in the research group, mutations that shorten the sequence of chemical bases in the CKR-5 gene are probably present in about 10 percent of Americans, and about 1 percent of them may inherit that kind of alteration from both parents.

The new findings provide strong evidence that future drug treatments targeting the CKR-5 protein or its gene might well help people to keep the AIDS virus in check if they become infected, O'Brien said yesterday.

"Today's finding points out a different but naturally proven angle from which to attack the virus and make its life really tough," O'Brien said in a statement released by the cancer institute.
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