UT-ORNL and UCSD Researchers Find Promise in HIV ‘Switch’

KNOXVILLE — If the battle against HIV, the virus that causes AIDS, is a chess match, then new research gives new insight into one of the virus’ most important moves.

The findings — by University of Tennessee, Knoxville, and Oak Ridge National Laboratory researchers Michael Simpson and Roy Dar, with colleague Leor Weinberger, who led the research at the University of California, San Diego — reveal new information about how a critical genetic switch in the virus operates. The findings are published as a letter in the upcoming issue of Nature Genetics.

When HIV infects an immune cell, it can enter one of two states: activation, where the virus replicates and then destroys the host cell; and latency, where the viral genetic material continues to exist in the cell, but there is no production of additional virus.

“While latency is a ticking time bomb,” said Simpson, “a possible therapeutic goal could be to stably maintain latency indefinitely.”

Previous work by Weinberger found that the genetic circuit that controls whether HIV chooses to go active or latent is not a simple “on-off” switch, but instead is controlled by a type of genetic pulse: When the pulse lasts a certain amount of time, the switch will activate replication of the virus.

Now the three researchers have demonstrated that it is possible to manipulate the lengths of the pulses in a way that would favor the selection of latency.

This is vital, said Simpson, because the switch is a definitive factor in whether the virus will become active. If the pulse does not last long enough, he said, the virus cannot become active.

“This is an early step, but an encouraging one,” said Simpson. “HIV has evolved a very effective infection strategy, so the name of the game is understanding how that strategy operates in order to find a way to defeat it.”

A challenge of the work, according to Simpson, is that the process involved in how the switch operates cannot be directly observed. Instead, the researchers had to rely on an analysis of the “noise” created within the cell by the process to determine how it worked.

Simpson and Dar conducted their work in the Center for Nanophase Materials Science at ORNL, a recently opened facility that Simpson says has made this type of analysis possible.

Moving forward, the next step in the research is to determine whether it is viable to attempt to control the switch as part of therapeutic treatment for HIV. The researchers also hope to apply the techniques they used to understanding the operation of other types of human cells.

The article is available online at http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.116.html.


Contacts:

Jay Mayfield (865-974-9409, jay.mayfield@tennessee.edu)

Michael L. Simpson (865-974-3316 or 865-574-8588, simpsonml1@ornl.gov)