Researchers report in this week's issue of Science that they have identified an innocuous, but relatively common, gene alteration that delays the onset of AIDS on average two to three years in people who are HIV positive.*
This finding, based on the analysis of 3,003 people whose HIV status has been tracked over many years, marks the report of a second gene that hinders HIV-1 when it is mutated. The researchers estimate that the newly identified mutation in the CCR2 gene is present in 20 to 25 percent of Americans and occurs at comparable frequencies in all races.
Combining CCR2 and CCR5, the other gene that when altered has been shown to be protective against HIV-1 disease progression, the researchers say that they now can explain why 30 percent of long-term HIV survivors avoid AIDS. They say the answer is found in their genes.
Likewise, the scientists say that they now know that about 40 percent of HIV-positive patients who succumb rapidly to AIDS do so because of their genes. However, they said that commercial testing for these mutations would be premature until the impact of several factors, such as the influence of other genes or strains of the virus, can be explored.
But Stephen O'Brien, Ph.D., leader of the AIDS genetics research group at the National Cancer Institute's (NCI) Frederick Cancer Research and Development and senior author on the paper, noted that these findings have clear implications for the treatment of AIDS. "These gene alterations tell us that nature already has devised a therapy that works without significant side effects," said O'Brien, "If we can pinpoint how these altered genes contain HIV-1, it may be possible to use this knowledge to develop treatments that help people delay the onset of AIDS."
This finding validates the critical importance of basic research in our nation's laboratories," said Donna Shalala, secretary of the U.S. Department of Health and Human Services. "These scientists have added a valuable new piece to the puzzle of HIV infection, one that clearly could lead to new treatments that help people who are HIV positive."
This paper is the latest from a flurry of research into chemokine receptors, a family of proteins that reside on the surface of immune cells. Last year, several research groups, including the authors of this week's article, determined that people exposed to HIV-1 in most cases don't become infected if they have a characteristic deletion in both copies of the chemokine receptor gene, CCR5. In those with a a deletion in only one copy of the gene, the onset of AIDS typically is delayed by a few years.
Since these landmark studies, laboratory investigations have suggested that other chemokine receptors, including CCR2, may play a part in the life cycle of HIV-1. "From all indications, there are going to be other receptors that interact with HIV-1," said Michael Smith, Ph.D., an NCI scientist and a lead author on the paper. "So, there's bound to be other gene alterations present in the human gene pool that influence HIV's ability to infect immune cells and cause AIDS. We just have to find them."
Using 3,003 DNA samples from five well-established AIDS cohort studies, Smith and his colleagues began screening for mutations in several chemokine receptor genes. After gene typing the full-length of the CCR2 gene in numerous samples, the researchers noticed a subtle change that kept reappearing in which the amino acid isoleucine was substituted for the normal amino acid valine. They named the alteration CCR2-64I.
"At first, I thought this shift was innocuous because typically these sorts of amino acid substitutions don't inactivate the protein," said Michael Dean, Ph.D., an NCI scientist and a lead author on the study. "It seemed so trivial in comparison to the CCR5 deletion, which omits a big chunk of the CCR5 receptor.
But Smith wasn't so sure. He decided to test whether CCR2-64I had an influence on the rate of progression to AIDS among a subgroup of 891 people with documented dates of HIV infection. Smith soon discovered that those who had the mutation in one or both copies of CCR2 consistently postponed the onset of AIDS by two to three years.
Smith, Dean, and their colleagues followed up with an analysis of 1,746 people divided into two groups: rapid progressors to AIDS (three years or less) and those who were slow or non-progressors (avoided AIDS for six to 12 years after infection). They found that although some of those who progressed rapidly to AIDS had CCR2-64I, the frequency of the alteration increased 30 percent to 85 percent among the slow progressors, depending upon the analysis performed.
But their results raised an important question. The researchers knew that CCR2 sits right next to CCR5 on chromosome 3. Was it possible that the protective effects that they were associating with CCR2 were really emanating from a deletion in the nearby CCR5 gene?
To answer this question, the scientists went back to 2,916 DNA samples and genotyped CCR2 and CCR5, that is, they spelled out and compared changes in the sequence of both genes in each of the samples. That's when they made a critical discovery: When CCR2-64I was present on a chromosome, CCR5 was always normal and free of mutations; likewise, when CCR5 contained a deletion, the CCR2 gene was always normal adjacent to it on the same chromosome. "This meant that both alterations had to be acting independently of one another to delay the onset of AIDS," said Mary Carrington, Ph.D., an NCI scientist and also a lead author on the paper. "They never appeared together on the same chromosome and seldom occurred on the opposite chromosome of the same person."
Carrington said she and her colleagues next compared the CCR2-64I alteration with a protective single deletion in CCR5. They found that both alterations had about similar effects, delaying the onset of AIDS on average two to three years. The group then estimated from its data that about a quarter of long-term survivors, those who have avoided AIDS 16 years or longer, have changes in either CCR2 or CCR5.
"Just a few years ago, there was still quite a bit of discussion about whether genes could be found that might explain the variable rates of progression to AIDS," said O'Brien. "Now we know there are genes and that genetic approaches can play an important role in understanding HIV."
This 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 National Cancer Institute, and the National Institute of Child Health and Human Development.
* The title of the study is "Contrasting Genetic Influence of CCR2 and CCR5 Variants on HIV-1 Infection and Disease," article dated Aug. 15, 1997. The authors are Michael W. Smith, Michael Dean, Mary Carrington, Cheryl Winkler, Gavin A. Huttley, Deborah A. Lomb, James J. Goedert, Thomas R. O'Brien, Lisa P. Jacobson, Richard Kaslow, Susan Buchbinder, Eric Vittinghoff, David Vlahov, Keith Hoots, Margaret W. Hilgartner, Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, and Stephen J. O'Brien.
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