Monday night, the 37th annual meeting on retroviruses at Cold Spring Harbor Laboratory started with its first session. The meeting, which takes place here from May 21-26, covers all aspects of retrovirology, although most presentations are on HIV. With 120 talks and almost 200 posters in five days, the meeting is “an intense experience,” said Vineet KewalRamani of the National Cancer Institute in Frederick, Maryland, one of the co-organizers this year.
An intense experience indeed: The first session on evolution ended at 11:15 pm. But the talks were more than interesting enough to keep everyone awake. One example came from Nicholas Meyerson from the University of Texas at Austin, who uses an evolutionary comparison of protein sequences from different species to identify HIV cofactors—host cell proteins the virus uses to complete its life cycle but that also have other functions for the host cell itself. “We are using evolution to try and identify the critical areas in the cell that HIV uses to infect us,” Meyerson said.
The approach is based on the assumption that the interaction between HIV and its host is like an evolutionary arms race similar to the game of rock-paper-scissors, Meyerson said. Certain parts of the cellular host proteins HIV interacts with most directly are constantly evolving mutations as an escape response, and once the virus responds with escape mutations on its own, “the game starts all over again,” he said. As a result, the parts of cellular host proteins that interact with HIV most directly would be expected to evolve most rapidly. “We are looking for regions that are evolving far more rapidly than they should be,” he said.
And indeed, Meyerson and his colleagues seem to have found such regions. For example, a comparison of the amino acid sequences of the CD4 receptor of 24 nonhuman primate species and humans revealed eight short sequences that change much more rapidly than the rest of the protein, and all eight are located in the parts of CD4 that are known to interact with HIV gp120. “The sites we uncovered are all around that [CD4-gp120] interface,” Meyerson said. “We believe that the signatures we have identified are due to direct physical contact with the virus.”
This is a proof of principle that the strategy works. But the researchers are also using the approach to identify other cellular cofactors that haven’t yet been shown to directly interact with HIV. A screen of hundreds of cofactors has so far identified eight that are “definitely engaged in this kind of arms race,” Meyerson said.
The approach doesn’t work in all cases, however. That’s because some cellular cofactors have so many other functions in the host cell that they can’t afford to mutate much, Meyerson said.