A protein that the body uses to attack the AIDS virus is actually a stealthy defense mechanism that evolved 32 million years before the emergence of HIV, according to new findings from Fred Hutchinson Cancer Research Center.
The research, by Harmit Malik, Ph.D., and colleagues in Fred Hutchinson's Basic Sciences Division, is available on the Public Library of Science Web site and will appear in the journal's September print edition.
The work hinges on a recently discovered protein called Apobec3G, which has been generating some buzz in the scientific community for its potential in shedding light on the genetic mechanisms of HIV prevention. The protein defends cells from HIV infection by causing mutations in the genetic material within the virus. In response, HIV produces a protein that binds to Apobec3G and targets it for destruction.
Such conflicts, often dubbed "genetic arms races," typically put pressure on both sparring partners to continually evolve new ways to outsmart and overcome each other just to stay in the game. Such genetic tugs of war also exemplify what is known among evolutionary biologists as the Red Queen Principle, a phrase borrowed from the Red Queen in Louis Carroll's "Through the Looking Glass" that refers to the paradox of running as fast as you can just to stay in place.
When comparing human Apobec3G genes with those of man's distantly related primate relatives, Malik and colleagues found, to their surprise, that the protein began to evolve in response to such Darwinistic pressure more than 30 million years before HIV-like viruses first infected primates, an event that occurred about a million years ago.
"This suggests that HIV is a newcomer to this conflict," Malik said, "because the host can't evolve a completely new defense in such a short period of time."
The discovery of Apobec3G's continual evolution — the result of the first detailed glimpse into the workings of a genome-defense system in which both parties to the conflict have been clearly identified — suggests that some forms of the protein are more effective at overcoming HIV infection than others, which may influence whether a person's disease advances rapidly, said Michael Emerman, Ph.D., an HIV researcher in the center's Human Biology and Basic Sciences divisions and a co-author of the study.
"There is great variation in disease progression among HIV-infected individuals," he said. "This variability is influenced by the type of virus that infects a person as well as by the person's genetic makeup. Increasingly, human genes are being discovered that influence viral progression. Apobec3G is a good candidate to be one of these genes."
The findings are a striking example of what can be learned from studying rapidly evolving proteins, the research approach taken by Malik's lab. Conflicts in nature drive this type of evolutionary change when two competing biological interests come head to head. Predators and prey often influence the evolution of one another, and the same can happen between viruses and proteins of the cells they infect.
"We don't always know what the conflict is, but by looking for proteins that are rapidly evolving in response to selective pressures we can identify candidates that participate in conflict," Malik said. "Some of them will be relevant to disease."
To identify the selective pressure on Apobec3G evolution, Sawyer and colleagues analyzed the genes from 12 primates — New World monkeys, Old World monkeys, great apes and humans — spanning 33 million years of evolution. This approach allowed them to backtrack through evolution and identify recent genetic changes a well as construct a hypothetical ancestor of all the species.