Understanding Primate Evolution Could Aid HIV Research

A few years ago, researchers discovered that a gene called TRIM5 allows most primates to inhibit the human immunodeficiency virus and other retroviruses, which use reverse transcription to insert themselves into their host’s genome. It turns out that TRIM5 exists in all primates, humans included, and that it’s involved in a rapid evolutionary back and forth with retroviruses: Each species has a unique TRIM5 gene that has evolved to deflect retroviruses, and each retrovirus has mutated in different ways to evade it in its particular host.

One change in particular, the insertion of a protein called cyclophilin into the owl monkey’s TRIM5 gene to create a hybrid TRIMcyp protein, has proven surprisingly potent at blocking HIV. Now, a study published online by the Proceedings of the National Academy of Sciences shows that in the pigtail macaque, the same protein inserted in nearly the same place had the opposite result — pigtail monkeys are curiously vulnerable to the virus.

Paul Bieniasz, head of the Laboratory of Retrovirology and an ADARC scientist, and ADARC assistant professor Theodora Hatziioannou discovered the monkeys’ susceptibility while examining cells from different species of primates to determine their reaction to HIV and other retroviruses. Surprised that one species of macaque could be so different from another in its ability to resist HIV, the researchers probed deeper.

First, they determined that pigtail macaque cells could fight off other retroviruses, such as the simian and feline relatives of HIV. Then, Bieniasz and Hatziioannou added cyclosporin, a drug that interacts with cyclophilin, to the equation and looked to see whether it affected the pigtail cells’ viral interactions. (The drug is known to overcome the ability of owl-monkey TRIMcyp to fight off the virus.) Sure enough, cyclosporin affected their capacity to fight off the simian and feline retroviruses. “That suggested to us that there was, perhaps, a protein like the owl-monkey TRIMcyp in these monkeys,” Hatziioannou says.

The researchers isolated the pigtail macaques’ TRIM5 gene and found that, like the owl monkeys, the pigtails also had cyclophilin inserted into their TRIM5 gene, though it was found at a slightly different location. Not only that, but there’s a single amino acid change in the pigtail cyclophilin, a tiny modification that appears to dictate whether or not the monkeys can inhibit HIV.

What surprised the researchers even more is that TRIMcyp is present in monkey species that evolved on different continents. Pigtail macaques live primarily in Southeast Asia, owl monkeys only in Central and South America. “This indicates that an intuitively unlikely evolutionary event occurred not only once but twice, in two primate species separated by 35 or so million years of evolution,” Bieniasz says. “This is a remarkable example of evolutionary convergence, and it underscores the potent selection pressure that can be applied by retroviruses.” Not only that, but their finding has the potential to guide researchers toward an effective animal model of HIV infection — something the field currently lacks.

Proceedings of the National Academy of Sciences online: February 19, 2008 http://www.pnas.org/cgi/content/abstract/0709258105v1