Putting a deadly virus out of work
Getting your foot in the door is sometimes seen as the key to career success. For the up-and-coming virus, though, getting in is just the first step. Shortly after arriving in its cellular workplace, the microbe must stage a takeover, commandeering the cell’s machinery to make copies of itself, then find its way out and repeat the whole process in another cell.
It’s the latter part of the process, the viral exit strategy, if you will, that intrigues Akira Ono.
“What I’m trying to understand is how viruses get ready to leave and how they get out,” says Ono, whose research focuses on HIV, the virus that causes AIDS. By zeroing in on these later stages in the viral life cycle, he hopes to find new targets for attacking HIV.
Like other viruses categorized as retroviruses, HIV stores its genetic material in the form of RNA (ribonucleic acid) instead of the familiar DNA used by almost all other organisms. Once HIV arrives on the job, it unpacks its tool kit, which includes a trio of enzymes: reverse transcriptase (RT), integrase and protease. RT performs the nifty trick of converting viral RNA into DNA. The DNA is then whisked away to the command center of the infected human cell“the nucleus”where integrase sneaks the viral DNA into human DNA, tricking the cell into manufacturing components for new viral particles. These components are then assembled into viral particles, after which protease helps the virus complete the maturation process.
Current drug treatments for HIV/AIDS inhibit RT and protease, and while these medicines have been remarkably successful in prolonging lives, HIV is a wily virus that constantly changes itself in ways that increase its resistance to existing drugs. One strategy for dealing with its mercurial tendencies is to keep developing similar, but slightly different drugs aimed at RT and protease. “But maybe,” suggests Ono, “a more effective method is to target other steps,” such as the final stages in assembly and exit, which take place at the outer membrane of the human cell.
Because a viral protein known as Gag is a major player in those steps, Ono is especially interested in its interactions. Gag, he has learned, latches onto a particular lipid, PIP2, in the membrane. Once attached to the membrane, Gag interacts with other Gag proteins to make a new virus particle, which exits through the membrane.
“Gag and PIP2 fit together like a key and keyhole,” says Ono. “Now that we know how crucial that interaction is, we want to find ways of interfering with it. But first we need a better understanding of exactly how the key and keyhole fit together.”
As his lab investigates that question, Ono also is exploring how the virus “hops from one cell to another.” This occurs in lymph nodes, where the white blood cells that HIV infects are tightly packed together. Interestingly, Ono has found, Gag has a habit of accumulating at the so-called “sticky ends” of these cells—the points where they come into contact with one another.
“If we can block Gag’s movement to that part of the cell, maybe we can block its transmission from cell to cell,” he suggests. And if that becomes possible, perhaps HIV will be out of work.
