While many may be deadly, the aim of the game for viruses is not actually to kill the host. Well, not straight away, anyway. A dead host is a dead end as it can’t keep transmitting the pathogen to new hosts. Obviously, if it’s causing trouble, the host will want to get rid of it, rallying defense mechanisms that have evolved over time. Now the virus has to adapt and fight back, selecting advantageous mutations that thwart the host’s.

This ongoing genetic struggle, or evolutionary arms race, can help us to paint a picture of the relationship and interactions between a virus and its host over time, and scientists have now used it to gain an insight into the past of HIV’s close relatives. According to new research, these lentiviruses have been infecting African primates for up to 16 million years, significantly longer than some previous estimates.

Coming to this conclusion was not easy. As lead researcher Welkin Johnson from Boston College explains to IFLScience, the problem with viruses is that they don’t leave fossils for us to look at. “There are no bones or tools that you can find to prove that they were there.”

In the absence of direct evidence of a virus’ history in its host, scientists go about it indirectly by looking at the historical interplay between viral genes and those in the host that are known to interact with them. For this particular study, the researchers chose to look at a host gene called TRIM5, a so-called “restriction factor” that evolved specifically to recognize retroviruses, the family to which HIV and its primate equivalent SIV belong, both of which are a type of lentivirus.

The TRIM5 protein protects host cells from infection by sticking to the virus’ protective shell, likely a conserved area that’s required for infectivity. Due to this restriction factor’s unusual specificity for retroviruses, the scientists reasoned that its evolution in African monkeys should bear the scars of selection by lentiviruses closely related to those present today. These genetic imprints can then be used to infer how long the viruses have been infecting their host species.

To turn back the clock and look at TRIM5’s evolution, the researchers analyzed its DNA sequence in 22 primate species from Africa, some that are naturally infected with these SIV lentiviruses and some that aren’t. By lining up these sequences and comparing them, the researchers were able to see how they were related to one another going back in time. This revealed a cluster of adaptive changes that were found at a specific site in the TRIM5 of multiple species belonging to a group called the Cercopithecinae, which includes macaques and mangabeys, the researchers report in PLOS Pathogens.

“These mutations seem to only impact whether TRIM5 could block primate lentiviruses, but not other retroviruses or other lentiviruses outside this group of species,” lead author Kevin McCarthy told IFLScience.

The fact that two independent primate lineages had resistance-conferring mutations at the same site led the researchers to conclude “that primate lentiviruses are ancient, going back maybe 11 to 16 million years ago,” McCarthy added.

The scientists then reconstructed ancestral TRIM5 genes and inserted them into cells, comparing them to sequences found today, and exposed them all to a panel of retroviruses, including some lentiviruses. This confirmed that the previously discovered cluster of mutations conferred specific resistance to lentiviruses of the Cercopithecinae group.

“It’s a nice piece of work,” virologist Jonathan Stoye, who was not involved in the research, told IFLScience. “But there is a central problem of how a molecule like TRIM5 can recognize multiple viruses which are rather different from one another. This continues to be unsolved.” 

^{Image in text: Model of a retrovirus capsid (shell) protein showing the most conserved area (circle) and a pocket of additional sites thought to affect recognition by primate TRIM5 proteins (arrow). Johnson et al., CC-BY.}