Sunday, March 13, 2005

Can past epidemics explain HIV resistance in Europeans?

There's a fascinating blurb in Nature news examining whether past epidemics which killed many Europeans can explain the prevalence of a mutation which confers resistance to HIV. At least 10% of Europeans, ranging from 4% of Sardinians to nearly 16% of Finns, have a mutation in a protein called CCR5, which HIV needs to infect macrophages and CD4 positive T-cells. (People homozygous for this mutation,called CCR5-delta32 , do not express any CCR5 protein on the surface of their macrophages. People heterozygous for CCR5-delta32 also have improved HIV resistance. The mutation is not cost-free, as it results, for example, in decreased responses to M. Tuberculosis.)

CCR5-delta32 appears to be relatively new in evolutionary terms (estimated origin in a single individual 1000-5000 years ago). This recentness may account for why the mutation is virtually absent outside of Europe. But conversely it becomes hard to understand how it got so prevalent within Europe. It must have come under huge positive selective pressure, meaning at some point people carrying the mutation must have out-survived their neighbors with normal CCR5.

One possible explanation is that this mutation helped Europeans survive during an earlier epidemic. For this to be the case, the epidemic would have to be devastating, cyclical, and have persisted in Europe for centuries. Nature cites a recent Hypothesis Essay in the Journal of Medical Genetics which proposes that the bubonic plague (Black Death), which dogged Europe from about 1350 into even the 1800s, could be the pest. This hypothesis, which has been around since the late 90's, is now revisited with a model of how the wheres and whens of the outbreaks, including the late persistence of bubonic plague in Scandinavia, might match a steady increase in the frequency of CCR5-delta32.

Two major problems with this idea are that bubonic plague is attributed to a bacterium, Y. Pestis, not a virus; and moreover CCR5-delta32 does not confer resistance against Y. Pestis infection. The bubonic plague proponents hypothesize that a virally borne hemmorhagic fever (not bacterial plague) may have contributed to the lethality of the Black Death, and thereby increased survival of people carrying CCR5-delta32. This idea is really threading a needle. The European mass graves from the time of the Black Death are absolutely crawling with Y. Pestis DNA. Resistance to a hypothetical virus would have trouble generating positive selection in the documented presence of a second massive killer, the bacterial plague, which is not affected by the mutation.

A second group believes that smallpox, a viral disease, may have been the guilty party. Poxviruses infect lymphocytes via a close relative to CCR5, so cross-resistance is easier to imagine. A difficulty with this hypothesis is that smallpox never appeared so cataclysmic as the Black Death, and may not have been sufficiently lethal, in population terms, to account for the prevalence of CCR5-delta32. Proponents of the smallpox theory counter by saying that the disease primarily killed children, who may not have made it into historical accounts; and that the cumulative effect of small scale smallpox epidemics over 700 years (lasting into the 20th century) killed far more than the Black Death did. I have to say, on balance, that their idea seems easiest.

One fascinating remaining observation is that sooty mangabeys, for whom SIV infection does not result in AIDS, also appear to control their CCR5 levels. . This receptor, then, could be a good target for efforts to prevent HIV infection.

Brief coda: The Telegraph claims that the CCR5-delta32 mutation arose somewhere in Mesopotamia. Impossible! Regardless of whether the mutation interferes with smallpox or Black Death, both diseases were widespread enough that CCR5-delta32 should have increased survival throughout southwest Asia. It has only been found in tiny percentage of people in Pakistan and the Middle East.

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