Scientists Confirm Natural Resistance to HIV-1

In August, AIDS researchers received some good news when two teamsof scientists reported that people born with changes in both copiesof a gene called CKR5 seem to have a natural resistance to HIV-1infection.

Now, taking this landmark finding one step further, another teamof researchers confirm, in the September 26th issue of Science,that people who inherit two altered copies of the CKR5 gene avoidHIV infection even after being exposed to the virus many times.The scientists found that the 17 people in the study exposed toHIV-1 who had dual mutations in CKR5 were free of HIV infection,strongly suggesting that they have a natural resistance to thevirus.

In addition, the scientists report that people who have one normaland one altered copy of CKR5 do become HIV-positive, but theytend to progress slowly to full-blown AIDS and often live longerthan most people infected with the virus.

These findings, which come from analyzing the DNA of 1,955 peoplewhose HIV status has been tracked for many years, provides thestrongest evidence to date that treatments targeting CKR5 and/orits protein could help people infected with HIV-1 keep the virusin check.

"Now that we are beginning to see the benefits of attackingHIV with, not one, but a combination of different drugs, [this]finding points out a different, but naturally proven, angle fromwhich to attack the virus and make its life really rough,"said Stephen O'Brien, PhD, leader of the AIDS genetics researchgroup at NCI's Frederick Cancer Research and Development Centerand senior author of the study.

According to Michael Dean, PhD, and Mary Carrington, PhD, coprincipalauthors of the paper and scientists at NCI's Frederick CancerResearch and Development Center, their study also confirms a previousreport that the most frequent mutation in CKR5, a short deletionin the gene, is probably present in about 10% of Americans.

The new finding reported in Science offers a nice example of howresearch in the laboratory can lead quickly to new strategiesto help people fight HIV-1. Last June, researchers made headlineswhen they discovered that a strain of HIV believed to be importantin person-to-person transmission of the virus anchors to immunecells called macrophages in a very specific way. They determinedthat HIV not only anchors to the well-known CD4 protein that sitson the cell surface but also attaches to the CKR5 protein. Itmay be that HIV sticks first to CD4, then uses the CKR5 as a gatewayto enter macrophages.

Following up on this new lead, two research teams reported independentlyin August that they had found a key piece to the long-standingpuzzle of why some people exposed to HIV never become infectedwith the virus. They found that these people had slight misspellingsin both copies of a gene encoding the CKR5 protein. They hypothesizedthat these typographical errors in the gene lead to changes inthe shape of the CKR5 protein that, like changing the shape ofa lock, blocks HIV from binding to the CKR5 protein that it usesto enter macrophages.

New Gene Evaluated in a Large Number of HIV-Infected People

The new finding confirms these important results by evaluatingthe role of the CKR5 gene in a large number of people whose HIVstatus has been tracked from 8 to 18 years. All belong to groupsat high risk for HIV infection--hemophiliacs, sexually activehomosexual men, and intravenous drug users. Each group includesindividuals who are HIV-positive with AIDS, those who are HIV-positivebut do not have AIDS, and a relatively large number of peoplewho 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 valuablesin HIV infection and progression--such as age, ethnicity, modeof transmission--with the CKR5 gene. This would give them a clearerpicture of the gene's importance to HIV-1.

Of the 1,955 people whose DNA Dean et al tested, 282 had one alteredcopy of CKR5. Of these 282 people, 195 were infected with thevirus, suggesting that people bearing one deleted copy of thegene were not protected from HIV-1 infection.

With further analysis, the scientists discovered that those withone copy of the deletion progressed slowly to full-blown AIDSand lived 3 years longer on average than those with normal copiesof CKR5. While the scientists don't yet know why this is so, Deanspeculated, "It may be that people with one normal and onealtered copy of the gene produce a smaller amount of protein thatis 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 peopleexposed to the virus, it may be possible to keep HIV-1 outsideof 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-positivepeople with hemophilia, the deletion, which was found in 309 individuals,didn't seem to have as large an effect on the rate of progressionto AIDS as it did among homosexual men. HIV-1-exposed hemophiliacswith one deletion in CKR5 were almost equally distributed betweenrapid and slow progression to AIDS. "While this finding certainlyneeds to be followed up for clarification, its implication is[that] HIV-1 may follow a somewhat different course in peoplewith different routes of infection," said O'Brien.

The researchers also found that people with one CKR5 deletionwere just as likely to become HIV-positive as most people in thegeneral population. Previous studies had suggested that thesepeople might be less likely to contract the virus.

Dean said his group's research also indicates that health-careprofessionals should consider testing people who participate instudies of new HIV drugs for inherited changes in CKR5. The researcherssaid that these individuals represent a subgroup of HIV or AIDSpatients who have a different prognosis from other people.

Dean, Carrington, and O'Brien, whose laboratory has been searchinghuman DNA for genes that influence HIV-1 infection and progression,also found eight other possibly protective genetic changes inCKR5. The group reported that all of these changes were rare,occurring in a total of less than 1% of more than 600 tested DNAsamples.