In August, AIDS researchers received some good news when two teams
of scientists reported that people born with changes in both copies
of a gene called CKR5 seem to have a natural resistance to HIV-1
Now, taking this landmark finding one step further, another team
of researchers confirm, in the September 26th issue of Science,
that people who inherit two altered copies of the CKR5 gene avoid
HIV infection even after being exposed to the virus many times.
The scientists found that the 17 people in the study exposed to
HIV-1 who had dual mutations in CKR5 were free of HIV infection,
strongly suggesting that they have a natural resistance to the
In addition, the scientists report that people who have one normal
and one altered copy of CKR5 do become HIV-positive, but they
tend to progress slowly to full-blown AIDS and often live longer
than most people infected with the virus.
These findings, which come from analyzing the DNA of 1,955 people
whose HIV status has been tracked for many years, provides the
strongest evidence to date that treatments targeting CKR5 and/or
its protein could help people infected with HIV-1 keep the virus
"Now that we are beginning to see the benefits of attacking
HIV with, not one, but a combination of different drugs, [this]
finding points out a different, but naturally proven, angle from
which to attack the virus and make its life really rough,"
said Stephen O'Brien, PhD, leader of the AIDS genetics research
group at NCI's Frederick Cancer Research and Development Center
and senior author of the study.
According to Michael Dean, PhD, and Mary Carrington, PhD, coprincipal
authors of the paper and scientists at NCI's Frederick Cancer
Research and Development Center, their study also confirms a previous
report that the most frequent mutation in CKR5, a short deletion
in the gene, is probably present in about 10% of Americans.
The new finding reported in Science offers a nice example of how
research in the laboratory can lead quickly to new strategies
to help people fight HIV-1. Last June, researchers made headlines
when they discovered that a strain of HIV believed to be important
in person-to-person transmission of the virus anchors to immune
cells called macrophages in a very specific way. They determined
that HIV not only anchors to the well-known CD4 protein that sits
on the cell surface but also attaches to the CKR5 protein. It
may be that HIV sticks first to CD4, then uses the CKR5 as a gateway
to enter macrophages.
Following up on this new lead, two research teams reported independently
in August that they had found a key piece to the long-standing
puzzle of why some people exposed to HIV never become infected
with the virus. They found that these people had slight misspellings
in both copies of a gene encoding the CKR5 protein. They hypothesized
that these typographical errors in the gene lead to changes in
the shape of the CKR5 protein that, like changing the shape of
a lock, blocks HIV from binding to the CKR5 protein that it uses
to enter macrophages.
New Gene Evaluated in a Large Number of HIV-Infected People
The new finding confirms these important results by evaluating
the role of the CKR5 gene in a large number of people whose HIV
status has been tracked from 8 to 18 years. All belong to groups
at high risk for HIV infection--hemophiliacs, sexually active
homosexual men, and intravenous drug users. Each group includes
individuals who are HIV-positive with AIDS, those who are HIV-positive
but do not have AIDS, and a relatively large number of people
who have been exposed to the virus but are HIV-negative.
With access to so many people with well-documented health histories,
Dean said he and his colleagues could correlate known valuables
in HIV infection and progression--such as age, ethnicity, mode
of transmission--with the CKR5 gene. This would give them a clearer
picture of the gene's importance to HIV-1.
Of the 1,955 people whose DNA Dean et al tested, 282 had one altered
copy of CKR5. Of these 282 people, 195 were infected with the
virus, suggesting that people bearing one deleted copy of the
gene were not protected from HIV-1 infection.
With further analysis, the scientists discovered that those with
one copy of the deletion progressed slowly to full-blown AIDS
and lived 3 years longer on average than those with normal copies
of CKR5. While the scientists don't yet know why this is so, Dean
speculated, "It may be that people with one normal and one
altered copy of the gene produce a smaller amount of protein that
is able to serve as a doorway for HIV-1 to enter certain cells.
If we can learn how to block the doorway altogether in all people
exposed to the virus, it may be possible to keep HIV-1 outside
of some immune cells without a key to get inside."
An Exception to the Rule
Dean and colleagues did note an exception to the rule. Among HIV-positive
people with hemophilia, the deletion, which was found in 309 individuals,
didn't seem to have as large an effect on the rate of progression
to AIDS as it did among homosexual men. HIV-1-exposed hemophiliacs
with one deletion in CKR5 were almost equally distributed between
rapid and slow progression to AIDS. "While this finding certainly
needs to be followed up for clarification, its implication is
[that] HIV-1 may follow a somewhat different course in people
with different routes of infection," said O'Brien.
The researchers also found that people with one CKR5 deletion
were just as likely to become HIV-positive as most people in the
general population. Previous studies had suggested that these
people might be less likely to contract the virus.
Dean said his group's research also indicates that health-care
professionals should consider testing people who participate in
studies of new HIV drugs for inherited changes in CKR5. The researchers
said that these individuals represent a subgroup of HIV or AIDS
patients who have a different prognosis from other people.
Dean, Carrington, and O'Brien, whose laboratory has been searching
human DNA for genes that influence HIV-1 infection and progression,
also found eight other possibly protective genetic changes in
CKR5. The group reported that all of these changes were rare,
occurring in a total of less than 1% of more than 600 tested DNA