"Early on many scientists thought that the Rev-RRE axis was merely an on-off switch for the virus. However, our recent studies have shown that it functions more like a rheostat," said Marie-Louise Hammarskjold, MD, PhD, associate director of UVA’s Myles H. Thaler Center.
By describing the system as a rheostat, Hammarskjold and her colleagues are highlighting that the Rev-RRE axis can be set to different levels of "brightness" or activity. The study found that subtle genetic variations in this axis directly influence how efficiently the virus can export its RNA and, consequently, how quickly it can replicate.
David Rekosh, PhD, director of the Thaler Center, emphasized the direct link between this genetic variability and the clinical challenge of curing the disease. "We’ve known for some time that the Rev-RRE axis varied in activity," Rekosh said. "This study links it directly to how well the virus can replicate and re-activate from latency."
Understanding HIV’s Regulatory Machinery
The mechanics of the Rev-RRE axis are central to the virus’s survival strategy. The UVA study demonstrated that when a virus possesses a "low-activity" Rev-RRE axis, it faces a significant disadvantage in terms of replication speed. However, this apparent weakness is actually a survival advantage when it comes to evading a cure.
Viruses with lower Rev activity are more likely to enter a deep state of latency that is incredibly difficult to reverse. Because their "rheostat" is turned down so low, they do not respond easily to the signals that would normally trigger viral reactivation. This variability helps explain why, in clinical trials, some pockets of the virus are easily cleared while others remain stubbornly persistent despite the use of powerful "latency-reversing agents."
This discovery has profound implications for a popular cure strategy known as "shock and kill." In this approach, doctors use drugs to "shock" the latent virus out of hiding, forcing the infected cells to start producing viral proteins. Once the virus is active, the immune system or targeted therapies can then "kill" the cells and clear the reservoir.
The UVA research suggests that "shock and kill" has struggled in the past because it may not be powerful enough to overcome the low-activity Rev-RRE rheostat in many latent cells.
"Rev has often been overlooked in the context of latency, even though it’s essential for HIV replication. Our work helps explain why some current ‘shock and kill’ approaches struggle to fully reactivate the virus," said Godfrey Dzhivhuho, PhD, the other lead author of the study. "If a portion of the viral reservoir has low Rev-RRE activity, it will be more resistant to reactivation."
Dzhivhuho suggests that the next generation of HIV therapies may need to be "smarter." Instead of just shocking the virus, future treatments might need to specifically target and enhance the Rev-RRE axis, effectively turning the rheostat up to ensure a complete and robust reactivation. Only then can the "kill" phase of the strategy be truly effective.
