Payment for ancient debts

By Johnjoe McFadden, professor of genetics at the University of Surrey (THE GUARDIAN, 28/08/07):

Foot and mouth disease is devastating to livestock, but rarely affects humans. The ability of a virus to cause disease in one host but not another is a poorly understood but common phenomenon. Scientists have recently found the remnants of a virus present in the genomes of chimpanzees and gorillas but absent in humans. Humans, it appears, evolved resistance to this virus millions of years ago. Paradoxically, however, the evolution of resistance to that now extinct virus may have made us more susceptible to HIV today.

Monkeys and humans are infected by many different viruses. Some of them, called retroviruses, replicate in our DNA. This type of retrovirus infection sometimes leaves a characteristic remnant of the virus, called an endogenous retrovirus, in the chromosome of the cell it infected. Our own genome bears witness to many ancient epidemics. It is littered with viral relics, as are the chromosomes of our close relatives, the apes and monkeys, which carry an endogenous retrovirus called PtERV. Analysis of the virus indicates that it swept through both chimp and gorilla ancestral populations about 3-4m years ago. Yet, curiously, the human genome is free of it, despite the fact that our ancestors are thought to have shared an overlapping African habitat with the great apes at the same time.

A study recently published in the journal Science by a team led by virologist Michael Emerman at the Fred Hutchinson Cancer Research Centre in Seattle, Washington, attempts to discover how our ancestors escaped the epidemic that infected the apes.

The team’s aim was to resurrect part of the ancient virus from the chimp genome. But each of the multiple copies of the endogenous retrovirus was subtly different. Genes, like words, change with time; so in the millions of years since their separation, the relic viruses have all diverged from their common ancestor. To resurrect the original virus sequence the scientists used a technique familiar to linguists. Milk is lait, latte or leche, depending on whether you are in a France, Italy or Spain. Linguists comparing these words can reconstruct the original word in the ancestral language, which turns out to be pretty close to the Latin form, lacte. In a similar manner the virologists were able to reconstruct the ancient DNA sequence of the 3m-year-old virus from the chimp genome and then examine the host range of the ancient culprit.

The PtERV virus can only successfully infect an animal if it avoids destruction by a protein called TRIM5alpha. This protein acts a kind of gatekeeper for the cell. The scientists studied whether the ancient virus could pass through the ape or the human version of the protein gate. As expected, the virus derived from chimps was able to infect cells that had the gorilla version of the protein. However, when switched to the human form, the virus replication dropped a hundredfold. It appears that the human TRIM5alpha protein is able to block infection by the ancient virus, possibly accounting for how our ancestors resisted it millions of years ago.

HIV belongs to the same family of retroviruses as PtERV, so the scientists were also interested in finding out whether the gatekeeping activity of the protein would keep out the Aids virus. What they found was that although the modern human TRIM5alpha protein was very effective at blocking the ape virus, it was very poor at blocking HIV infection. Conversely, the ape form of the gatekeeping protein blocked HIV infection but allowed in the PtERV virus. It seems that when one door was closed to infection, another one was opened.

Michael Emerman’s team speculates that 3-4m years ago a PtERV epidemic swept through the African apes, including our ancestors. A chance mutation in at least one hominid, our ancestor, made it resistant to the virus scourge sweeping the continent. That mutation came at a hidden cost. It may have saved our ancestors from extinction, but it cast a shadow into the 20th century when a new virus, HIV, emerged. The gene that saved our ancestors from the ancient viral scourge provided little protection against the new virus.

The Aids epidemic is the price humanity is now paying for that ancient debt. It seems we cannot easily escape our evolutionary heritage.