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October, 1996

Genetic mutation appears to confer immunity to HIV

Evidence suggests that 1 in 100 is completely immune, and 1 in 5 is resistant to disease progression

Two questions have long intrigued those involved in the study of HIV disease and the treatment of infected patients: Why is it that some individuals remain seronegative despite repeated exposure to the human immunodeficiency virus? And why is it that HIV disease progresses rapidly in some exposed individuals and indolently in others? Researchers at the National Cancer Institute may have found an answer to both those questions. In a report published several weeks ago in Science, an N.C.I. team headed by Dr. Stephen J. O'Brien announced the discovery of a mutant gene, CKR5, that appears to confer complete immunity to HIV infection in roughly 1 individual in 100, and confers resistance to disease progression in 1 in every 5 infected individuals. The surprisingly high incidence of partial resistance could explain why some individuals survive for many years with active infection.

O'Brien et al. draw their conclusions from a study of 1,850 subjects at high risk of HIV infection: gay men who had unprotected sex on numerous occasions with men who were probably or certainly HIV-positive; injection drug users who shared equipment with infected individuals; and hemophiliacs who injected themselves with HIV-tainted blood products during the early years of the AIDS epidemic.

In this retrospective study of stored blood samples taken from subjects who had been repeatedly exposed to HIV, individuals who had inherited the CKR5 mutation from both parents enjoyed complete immunity from infection. Those who inherited the mutant gene from only one parent did develop HIV disease, but in these individuals disease progression was slowed by an average of three years.

Curiously, the N.C.I. researchers found this incidence of protective mutation only in white study subjects. Almost no blacks appear to carry this mutated gene, but the researchers suspect that other forms of genetic immunity to HIV may occur in blacks. Indeed, the N.C.I. team feels certain that other forms of protective mutation against HIV occur in all races. They draw this conclusion from the fact that the CKR5 mutation, prevalent as it was, accounted for only 3% of the resistance to HIV seen in the study.

(In a similar study conducted in Brussels, a team headed by Dr. Marc Parmentier found the double CKR5 mutation in 1% of 700 Caucasians but could not find the mutation in any of the 124 Africans or 248 Japanese in their study cohort.)

The identification of what may well be the key receptor for HIV infection has prompted considerable speculation about the potential therapeutic benefits of this discovery. Because the mutant gene is harmless in uninfected individuals, a drug that blocks the CKR5 receptor in the same way the double-mutant gene does might block HIV replication without producing toxic side effects.

One puzzling aspect of this discovery is why the CKR5 mutation exists at all, let alone why it is so prevalent. As a rule, mutations that alter or eradicate a gene are self-extinguishing, and mutations persist only if they confer a distinct survival advantage. Dr. David Baltimore has offered two theoretical explanations for the persistence of this particular mutation, and for its prevalence in whites but not blacks or Asians. The first is that the CKR5 mutation may have conferred resistance to other pathogens, notably bubonic plague, which killed roughly a quarter of the population of Western Europe in 1348 -- and may have endured in descendants of survivors of the so-called Black Death, virtually all of whom were Caucasian. The second potential explanation is that AIDS itself ravaged the same area of Western Europe many centuries ago, and the CKR5 mutation conferred a survival benefit then, just as it seems to do now.

Dean M, Carrington M, O'Brien SJ, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 1996; 273: 1856-62.

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