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December 4, 1998

For Unlucky Few, Gene Sends H.I.V. on Wild Stampede

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    Scientists have discovered why some people who are infected with the AIDS virus have a rapid downhill course, becoming gravely ill and dying within a few years, while most infected people live for years without major symptoms.

    The key is a gene that acts like a molecular rheostat, turning up or down the activity of another gene that produces a protein the AIDS virus uses as a doorway to enter cells. A normal variant of the rheostat gene turns out to accelerate the onslaught of the AIDS virus in about a fifth of people whose HIV infection progresses rapidly.

    About one person in 10 has the gene variant, which is described in a report in Friday's issue of the journal Science. As a result, said Dr. Stephen J. O'Brien, the head of the group that discovered the gene's effect, "if they get infected with HIV, they'll go fast." O'Brien is chief of the laboratory of genomic diversity at the National Cancer Institute in Frederick, Md.

    Scientists say the discovery might help them devise treatment strategies, but not actual treatments for HIV. O'Brien said the discovery's immediate importance was in evaluating AIDS vaccines, because it was important to know a group's genetic susceptibility in deciding if a vaccine slowed the course of the disease.

    But, researchers say, the result is most significant as a harbinger of the future of disease research. It fleshes out a picture of HIV infections that illustrates how a gene that appears to have no obvious relationship to a disease can determine the outcome of the complex battle between the body, with all its cells and organs, and a disease.

    "AIDS is leading the way," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

    Doctors treating AIDS patients have long been interested in the unpredictable nature of the disease. While, on average, the time from infection with HIV to disease is about 10 years, there are people at either end of a wide spectrum.

    "People with HIV come to the clinic and could live for more than 15 years and be healthier than you or I," said Dr. Sunil Ahuja, an AIDS researcher at the University of Texas Health Science Center in San Antonio. Or, he said, "they could die two or three years later."

    With just a few years of concentrated effort, AIDS researchers have discovered genetic variations that normally have no consequence, yet can cause the most striking features of infections with HIV

    First they found genes that act like "a molecular condom," Ahuja said, protecting people from becoming infected. Then they found genes that determine whether people who are infected will be long-term survivors, those lucky 5 percent of infected people who go for more than 15 years without becoming ill.

    Now they have a gene that puts people at the other end of the spectrum, making them quickly succumb to HIV. And soon to appear, one group says, is research showing a gene that determines whether an infected woman will pass on HIV to her fetus.

    Of course, said Dr. John Moore, a researcher at the Aaron Diamond AIDS Research Center in New York, scientists had an advantage in their studies.

    From the beginning of the epidemic, thousands of patients have volunteered to be followed closely, providing cells for genetic analysis and medical records that would allow researchers to correlate their disease progression with their genetic inheritance. Those large groups of patients were the key to discovering the relationships of genes to the course of the disease.

    It is all but useless, Moore said, to look at an individual and ask why that particular person did, or did not, have a rapidly progressing infection. Scientists need to look at close to 1,000 individuals to see if a particular genetic pattern persists in people with particular disease patterns, he said.

    The current discovery builds on recent research showing that CCR5, a protein on the surface of cells, can act as a doorway for HIV. Then, about a year ago, Ahuja discovered genes that control the CCR5 gene, the so-called CCR5 promoter genes.

    Upon further investigation, O'Brien and his colleagues, including Dr. Maureen P. Martin and Dr. Mary Carrington, discovered that there were 10 genetic sites within the CCR5 promoter that varied from person to person, and each site had two possible genetic forms. That meant there were a total of 1,024 possible normal genetic variations of the gene.

    But, O'Brien said, when they looked for the variations in a group of 2,400 people, "mercifully, only four were common."

    O'Brien and his colleagues next examined genetic and medical data from 700 people who had been infected with HIV. Close to 15 percent had progressed rapidly to severe illness and death.

    Of them, 10 percent to 17 percent had a particular variant of the CCR5 promoter gene, the investigators found. The investigators expect that other, as yet undiscovered genes, will explain why the others deteriorated so quickly.

    O'Brien said he saw the growing understanding of how genes determine the course of an HIV infection in terms of an epic struggle between the virus and the human body.

    As a swarm of billions of viruses try to invade cells, they require collaboration from the body -- its cells, enzymes and molecular pathways that facilitate the course of the virus.

    At any stage, the body can throw up a roadblock and slow or prevent the viral attack. And at any stage, genes that control cellular functions that may seem only tenuously connected to infection with the AIDS virus can take on key roles.

    Dr. Kenneth K. Kidd, a professor of genetics and psychiatry at Yale University, said the AIDS scenario was typical of diseases in general.

    "Disease is not generally a single thing that goes wrong," he said. "It is a process, a multi-stage process, and many of the symptoms are results of secondary effects that develop later and affect another system."

    And so, he said, there are myriad ways for different genes to alter the course of a disease.

    With AIDS, said Dr. Gregory Stock, the director of the program on medicine, technology and science at the UCLA School of Medicine, "we are just beginning to see the kinds of things that will occur in many, many diseases."

    "It is going to be incredibly interesting," Stock said. "We're entering a renaissance."

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