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LONDON Several teams of scientists around the world have, for some time, been studying the possibility that a genetic mutation perpetuated by the organism responsible for bubonic plague, or the Black Death, in the Middle Ages - Yersinia pestis - might give people now carrying the mutation increased resistance to the Human Immunodeficiency Virus (HIV) compared to non-carriers. New research has thrown doubt on the micro-organism that was thought to have caused the Black Death, but the link to HIV resistance seems to remain.Sue Scott and Chris Duncan from the University of Liverpool have suggested that the bacterium Y. pestis — held to be the causative organism for bubonic plague since the 19th century — may not have been responsible for the epidemic after all. In their book, 'Biology of Plagues' (Cambridge University Press, 2001) they proposed that the culprit was most likely a filovirus, similar to the Ebola virus. This theory is based on evidence that emerged after sifting through old parish records of the many towns affected by the plague and then tracking how the disease spread throughout Britain and Europe. So how does this link to increased resistance to HIV? In a study published in the American Journal of Human Genetics (Am J Hum Genet 1998, 62:1507-1515) Stephen O'Brien and colleagues at the US National Cancer Institute, used coalescence theory to interpret modern haplotype genealogy. They found that a genetic mutation that gives its carriers protection against the HIV virus became relatively common among white Europeans about 700 years ago — the same period that the Black Death swept into Europe. The team also concluded that the geographic cline of the mutation frequencies and its recent emergence were consistent with a strongly selective historic event (such as an epidemic of a pathogen), driving its frequency upwards in populations whose ancestors survived the Black Death. The mutation occurs on the gene for CCR-5, a receptor on the surface of macrophages. When a person becomes infected with HIV, the virus latches onto CCR5 and another protein — CD-4 — to be transported inside the macrophages.CCR-5 is disabled in people with the full mutation, and so HIV is unable to gain access to the macrophages. If an individual inherits the mutant gene from both parents, they are essentially immune to HIV infection. People with one mutant and one normal gene can be infected, but tend to survive longer than infected people with two normal CCR-5 genes. It seems as though people without the mutation, called CCR5-Δ32, were killed by the Black Death, so that those with the mutation survived to reproduce and increase its prevalence today.In 2000, another team of scientists, from Copenhagen's Hvidovre Hospital, investigated why many Europeans appeared to be resistant to HIV. Jesper Eugen-Olsen teamed up with archaeologist and carbon-dating specialist Kaare Lund Rasmussen from the Danish National Museum and analyzed genetic material from ancient bone tissue to try to solve the mystery. "It always puzzled scientists in the field that the mutation never occurs in Asian or African populations, but only among European Caucasians," said Eugen-Olsen. It is much more prevalent in the North and tapers off towards the Mediterranean, meaning that only eight out of 100 Southern Italians carry the mutation, compared to one in four Danes.The Danish group rejected the idea that the mutation became more prevalent as a result of the Black Death because the epidemic began in Sicily (in the South) and spread north to Scandinavia. This direction of travel would have predicted that the prevalence of the mutation would have become higher in the South than in the North, which is the reverse of what actually happened.Assuming that the mutation arose in Scandinavia, Eugen-Olsen's team concentrated on determining the time of the major spread of the mutation by examining bones found in Denmark, dating from the last Ice Age, around 8000 BC to 1950 BC. In particular, they focused on the time between 1800 and 2600 BC, a Mesolithic period of massive change and migration.Their findings suggested that the CCR-5-Δ32 mutation was already highly prevalent in Denmark before the Black Death. Rasmussen reported: "There is support in the fact that the distribution of the Single Grave Culture in Northern and Middle Europe matches that of the high prevalence of 32Δ." This meant that an epidemic decimating the Stone Age population could explain the archaeological observations as well as the distribution of the 32Δ mutation.They proposed that people with the genetic mutation were then more likely to survive the Black Death, passing on the mutation to current generations and conferring resistance to HIV.Although the potential cause of the Black Death might have changed, researchers in the field still suspect that exposure to it may have passed on resistance to HIV. Since the CCR5 mutation provides protection against the entry of a virus, there's good reason to believe that what caused the Black Death was also viral, and targeted the same cells as HIV," concluded Scott.

Could the Black Death protect against HIV?

People who survived the Black Death could have passed on a mutation that prevents the human immunodeficiency virus entering cells.

Jul 12, 2001

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