Scientists Discover A Third Gene Alteration That Slows Progression to AIDS

National Cancer Institute
Thursday, 15 January 1998

Researchers report in this week's issue of Science that they have discovered a new human gene alteration that delays the onset of AIDS on average from seven to 10 years.

This finding, based on a genetic analysis of nearly 3,000 people whose HIV status has been tracked over many years, marks the discovery of a third gene alteration that slows the progression of HIV-1 infection. The researchers noted that the protective changes, which are needed in both copies of the SDF-1 gene (people inherit one alteration from each parent), occurred in fewer than 5 percent of those studied. This makes the SDF-1 alteration far less common than the two previously reported protective mutations in the CCR2 and CCR5 genes, which protect people carrying only one mutated copy.

"This finding shows that the HIV-1 virus and SDF-1 protein cross paths at a point in the virus's life cycle where it is vulnerable to attack," said Stephen O'Brien, Ph.D., leader of the AIDS genetics research group at the National Cancer Institute"s (NCI) Frederick Cancer Research and Development Center and senior author on the paper. "Now the challenge is to learn to initiate the protection and help people fight the virus more effectively."

This week's finding also could help to unravel one of the major unanswered questions in AIDS research. Why does HIV-1 virus linger in the immune system after infection for several years before it mounts its debilitating attack on immune T cells, triggering the onset of AIDS?

In recent years, scientists have hypothesized that the answer may be that new strains of HIV-1 evolve over time that can bind to proteins positioned on the surface of T cells, specifically a protein called CXCR4, and infect them. This theory, though popular among scientists, remains largely unproven.

Cheryl Winkler, Ph.D., a scientist with Science Applications International Corporation in Frederick, Md., and lead author of the study, said that one of the most intriguing aspects of the SDF-1 protein--a molecule that immune cells use to communicate with each other--is it normally binds to the CXCR4 protein that the more virulent HIV-1 strains use as one of their docking sites on the surface of T cells.

Winkler said the fact that so many people with two altered copies of the SDF-1 gene were long-time survivors of HIV suggests that changes in SDF-1 protein production can impede the virus from turning its attack against T cells.

But Winkler said this raises another intriguing point. She said the alteration, called SDF-1-3'A, involves a change in just one unit--or base--of DNA, and it occurs in a region of the gene that goes untranslated during protein production. In other words, the alteration has no effect on the protein product. The SDF-1 protein is normal in people with the alteration.

O'Brien said one interpretation is that SDF-1-3'A occurs in a region of the gene that may help to regulate the transport or production or persistence of the protein. He said it may be that the alteration increase the production of SDF-1. With more of the protein available to compete with HIV-1 for the CXCR4 receptor, the virus has a harder time binding and entering T cells.

"There is no direct evidence yet that this is the case," said O'Brien. "But this paper offers a very interesting lead in helping to delineate the process."

In this week's paper, Winkler et al. initially noticed the slight alteration, called a polymorphism, in a screen of the SDF1 genes in people from five well-established AIDS cohort studies. Subsequent screens in a larger number of cohort participants showed that the alteration is found in several racial groups and only weakly prevents people from becoming infected with HIV-1.

Winkler and colleagues then asked whether the alteration influenced a person's rate of progression to AIDS in a subgroup of 639 people with well-characterized dates of initial HIV infection.

Comparing people without the deletion to those who have a single copy of SDF1-3'A, the scientists noted no difference in how rapidly each group developed AIDS. However, among people with two copies of SDF1-3'A, they did notice a significant delay. They also found that the dual alteration was more frequently found among people who are classified as slow or non-progressers (avoided AIDS for six to 12 years after infection), further indicating a protective effect.

Upon further analysis, the scientists found that the effect of the protective mutation is more pronounced in the latter stages of HIV-1 infection, when new strains of the virus target T cells. "This suggested that the alteration influenced the virus's life cycle at or near the point where it turns extremely destructive," said Winkler. "CCR2 and CCR5 seem to be protective much earlier on in the infectious process, so the SDF-1 polymorphism was an extremely interesting find."

Winkler et al. next compared the two previously reported gene changes in CCR2 and CCR5 with those in SDF1. Their analysis reaffirmed the protective effects of all three genes. But it also showed that dual alterations in the SDF-1 gene are two to three times more effective in delaying AIDS than the other two gene changes.

They also found that among 10 people who have the dual SDF-1 polymorphism with either a CCR2 or CCR5 change, just one has progressed to full-blown AIDS. In those with both SDF-1 and a CCR5 mutation, very few have progressed to full-blown AIDS.

The work involved the cooperation of thousands of volunteers involved in five AIDS cohort studies: Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, ALIVE Study, Multicenter Hemophilia Cohort Study, and San Francisco City Cohort. These cohorts are supported by various NIH institutes including the National Institute of Allergy and Infectious Diseases, the NCI, and the National Institute of Child Health and Human Development.

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