Scientists Discover A Second Gene Alteration That Slows Progression to AIDS

"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 CCR2-641 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, PhD., 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 CCR2-641 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.

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