Tracking a master of disguise and deception
Viruses are notoriously crafty, constantly developing new ways to evade the immune system and outwit drugs designed to defeat them, but none is more devious than HIV, the virus that causes AIDS. Like a fugitive who constantly alters his appearance, HIV is known for its variability, which makes designing drugs and vaccines against it an enormous challenge.
Scientists once believed that most of that variability came from mutations—copying errors that arise during the process by which viruses reproduce. About one such error occurs during each round of replication, resulting in a panoply of closely related HIV variants. But in recent years, researchers have realized that another process, genetic recombination, is even more important in generating HIV diversity.
“The rate is almost ten-fold more frequent than mutations,” says Alice Telesnitsky, who is fascinated with the details and implications of recombination in HIV and other retroviruses.
Like other viruses, HIV can’t reproduce on its own; it must sneak its genetic information into the DNA of the cells it infects and trick those cells into reproducing viral genes and manufacturing viral proteins. Unfortunately for HIV, mistakes are made in the process, many of which are serious enough to inactivate the virus. But even when that happens, the scoundrel leaves behind a legacy: its defunct genes remain in the host’s DNA and are passed on genetically. Over time, all those slip-ups add up, says Telesnitsky. “About half of human DNA is actually retroviral mistakes.”
Distressing as that sounds, it wouldn’t be a problem if the inactive viral genes just sat there untouched for eternity. But when another HIV virus infects the same cell, that virus can “resuscitate” the dead genes left behind by its predecessor, through the process of recombination. The result is “a vast mosaic quilt of possibilities” for generating new variants, Telesnitsky says.
In addition to exploring recombination, Telesnitsky is looking into other ways HIV takes advantage of its host. One way is by exploiting cellular “machines” called RNPs. These complexes of RNA and protein include such well-known entities as ribosomes, where proteins are made, “but there are all sorts of other ‘machines’ for which the function is unknown—they’re just sitting there like a bunch of refrigerators, and we don’t know what they’re doing for the cell,” says Telesnitsky. It’s clear, though, that retroviruses commandeer the mysterious machines and use them to their own advantage.
“The viruses are using parts of these machines to make themselves, and we’re figuring out how they do that,” Telesnitsky says. Part of that effort involves understanding exactly which portions of the machine the virus interacts with. One particular RNP that Telesnitsky’s lab is studying is shaped like a dog bone, and while the lobes of the “bone” may be important in the RNP’s normal function, smaller features, like “warts on the side of the bone” may be what the virus cues in on. Identifying those features should make it possible to design drugs that prevent the virus from using RNPs without interfering with RNPs’ normal functions.
There also are hints that retroviruses, ever the masters of disguise, masquerade as host RNPs to escape undetected when it’s time to leave one cell and go off to infect others. By probing that process, Telesnitsky hopes to unmask the villains and halt their deadly spread.
