Research & Discovery

UVA Scientists Find New Clue in Quest To Cure HIV

University of Virginia School of Medicine scientists have uncovered a key reason why HIV remains so difficult to cure, bringing researchers closer to finding ways to flush out the dormant virus and eliminate it for good.

Their research shows small changes in the virus affect how quickly or slowly it replicates, and how easily or stubbornly it can reawaken from hiding.

Thanks to advancements in treatments, HIV can now be controlled so well it is nearly undetectable in the blood, eliminating most disease symptoms and preventing transmission to others. But HIV never truly goes away. It lies dormant in the body and can reemerge if medications are stopped. That’s how the virus evades antiretroviral drugs and the body’s immune system.

“HIV treatment is lifesaving but also lifelong,” said Dr. Patrick Jackson, one of the two lead authors on the paper detailing the discovery. “Understanding how the virus stays latent in cells could help us develop a lasting cure for HIV.”

Dr. Patrick Jackson and Godfrey Dzhivhuho

Dr. Patrick Jackson, left, and researcher Godfrey Dzhivhuho are co-authors of the study that found the mechanism that allows HIV to hide. (Photo by Matt Riley, University Communications and contributed photo)

UVA’s latest findings reveal a critical clue to how HIV controls its dormant state. The research shows subtle variations in a viral control system, known as the “Rev-RRE axis,” influence how efficiently the virus replicates and how easily it reactivates.

Some variations make the virus more aggressive. 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 Dr. Marie-Louise Hammarskjöld, associate director of UVA’s Myles H. Thaler Center for AIDS and Human Retrovirus Research. The center is 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, 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 small changes in this regulatory system directly impact HIV’s ability to replicate and reemerge. For instance, viruses with low Rev activity have a disadvantage in both replication and reactivation.

These findings help explain why HIV persists despite aggressive treatment. Researchers say to develop a cure, future therapies may need to account for these subtle variations that allow the virus to shift its behavior.

Portraits of Marie-Louise Hammarskjöld, left, and David Rekosh, right

Marie-Louise Hammarskjöld, left, is associate director of UVA’s Myles H. Thaler Center for AIDS and Human Retrovirus Research and David Rekosh is the center’s director. They also lead the HamRek Lab at the center where the research was done. (Contributed photos)

“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, the other lead author of the study. “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 Hammarskjöld, of the HamRek Lab in the Thaler Center, years ago when the researchers taught summer sessions at the University of Venda in Dzhivhuho’s native South Africa, where more than 8 million people live with HIV.

“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.”

The researchers have published their findings in the scientific journal PLOS Pathogens. The research was supported by the Myles H. Thaler Research Support Gift to UVA and by the National Institutes of Health.