In an unusual approach, researchers have resurrected an inactive chimpanzee retrovirus that was never able to infect humans. Test tube experiments suggest that humans paid a high cost for developing immunity to this bug: It may have left us much more susceptible to another retrovirus, HIV.
The study, which appears tomorrow in Science, focuses on Pan troglodytes endogenous retrovirus (PtERV1). More than 100 copies of inactive PtERV1 are sprinkled throughout the chimpanzee and gorilla genomes, whereas humans have none. "About 4 million years ago, this virus was active and independently infecting all these species, but not humans," says virologist Michael Emerman, who conducted the study with evolutionary biologist Harmit Malik and postgraduate student Shari Kaiser, all of whom work at the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Because ancient humans are thought to have lived in the same regions as these closely related apes, the researchers asked whether an antiviral factor in our cells might have thwarted PtERV1. They homed in on TRIM5α, a protein that protects against retroviruses and that exists in different forms in different primates.
To assess whether human TRIM5α could stop PtERV1, the investigators first had to bring PtERV1 back to life. They did this by stitching critical PtERV1 genes into a mouse retrovirus. The team then showed that this chimeric virus easily infected cat cells that had no TRIM5α but hardly caused any infection in cat cells engineered to contain human TRIM5α.
Among AIDS researchers, TRIM5α has attracted much attention because Asian macaques have a version of the protein that plays a key role in preventing their infection with HIV-1. Human TRIM5α, in contrast, does little to thwart HIV-1. This led Emerman and co-workers to test whether TRIM5α from other primates potently restricted both PtERV1 and HIV-1. None did. Time and again, it seemed, locking out one virus appears to have opened the door for another.
"I think it's a reasonable model system that's really neat and provides us with important insights into the never-ending battle between host and pathogen," says Thomas Hope, an AIDS researcher who studies TRIM5α at Northwestern University Feinberg School of Medicine in Chicago, Illinois. "They have really reeducated virologists about evolution."
Still, there are a few untidy aspects to the relationship between TRIM5α and PtERV1. For example, even though ancient chimps were susceptible to PtERV1, today's chimps seem resistant. Modern chimps have a humanlike version of TRIM5α, so the researchers postulate that it may have mutated from its ancient form long after the two species split. Or it could be that TRIM5α works in concert with other factors to block retroviruses. "This is just the beginning of trying to understand how the evolution of these genes has shaped modern viral susceptibilities," says Emerman.