University of Virginia School of Medicine scientists have uncovered a key reason why HIV remains so difficult to cure: Their research shows that small changes in the virus affect how quickly or slowly it replicates, and how easily or stubbornly it can reawaken from hiding. These insights bring researchers closer to finding ways to flush out the dormant virus and eliminate it for good.
Thanks to remarkable progress in HIV treatment, the virus can often be suppressed to undetectable levels in the blood, eliminating most disease symptoms, and preventing transmission to others. But HIV never truly goes away. Instead, it hides in the body in a dormant, or “latent,” state, and if medications are ever stopped it can reemerge. In this stealth mode, the virus evades both antiretroviral drugs and the immune system, posing one of the biggest challenges to finding a cure.
“HIV treatment is lifesaving but also lifelong,” said Patrick Jackson, MD, one of the two lead authors on the paper. “Understanding how the virus stays latent in cells could help us develop a lasting cure for HIV.”
UVA’s new findings reveal a critical clue to how HIV controls this hiding act. The research shows that subtle variations in a viral control system, known as the Rev-RRE axis, influence how efficiently the virus replicates and how easily it reactivates from latency. Some versions of this system make the virus more aggressive, while others keep it less active and harder to bring out of hiding for elimination.
“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 for AIDS and Human Retrovirus Research in the Department of Microbiology, Immunology and Cancer Biology.
“We’ve known for some time that the Rev-RRE axis varied in activity,” said David Rekosh, PhD, director of the center. “This study links it directly to how well the virus can replicate and re-activate from latency.”
Understanding HIV
To replicate, HIV must export its RNA — its cellular operating instructions — from the nucleus of infected cells. It does this using a coordinated system involving a viral protein called Rev and a special RNA structure called the Rev Response Element, or RRE. UVA’s new research shows that small changes in this regulatory system directly impact HIV’s ability to replicate and emerge from latency. The study found that viruses with low Rev activity had a disadvantage in both replication and latency reactivation.
This variability helps explain why HIV persists despite aggressive treatment. To develop a cure, future therapies may need to account for these subtle variations that allow the virus to shift its behavior, the researchers say.
“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. By enhancing the Rev-RRE axis, we may be able to induce a stronger and more complete latency reversal and bring us closer to strategies that can truly clear the virus.”
Dzhivhuho first met Rekosh and Hammarskjold years ago when they were teaching summer sessions at the University of Venda in South Africa, a country where more than 8 million people live with HIV. He later obtained his PhD in HIV immunology from the University of Cape Town and now devotes his career to better understanding HIV and other infectious diseases as part of UVA’s Thaler Center.
“Coming from South Africa, where HIV affects so many lives, I’ve always wanted to be part of the effort to end this epidemic,” Dzhivhuho said. “I hope this work brings us one step closer to a cure, not just by uncovering how the virus works, but by helping design smarter strategies to finally eliminate it. That’s what drives me every day in this research.”
This work was supported by the Myles H. Thaler Research Support Gift to UVA and by the National Institutes of Health, grants R21 AI134208 and K08 AI136671.
