Scientists Confirm Natural Resistance to HIV-1

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 infection.

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 virus.

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 in check.

"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 samples.