Small Molecule Appears to Destroy Protein That Wakes Dormant HIV


A team of researchers in California found a way to short-circuit the protein that would otherwise allow HIV to wake from dormancy.

Katherine Jones, PhD, a professor in the Salk Institute Regulatory Biology Laboratory

Katherine Jones, PhD, a professor in the Salk Institute Regulatory Biology Laboratory

Katherine Jones, PhD

Scientists have discovered a way to inhibit the activation of dormant HIV cells, in what could be a first step toward a functional “cure” for the virus.

Researchers at the Salk Institute, in California, made the discovery while investigating HIV proteins. One of those proteins, Tat, is responsible for triggering and accelerating the copying of the virus after dormancy. In other words, Tat seems to be key in waking up HIV. In researching the proteins, the scientists discovered something unexpected—a small molecule named JIB-04 seemed to destroy Tat.

Closer inspection showed that JIB-04 binds together 2 enzymes in the host cell, SHMT2 and BRCC36. Those enzymes help save proteins that the cells have “flagged” for destruction, in this case, Tat. By binding those enzymes together, JIB-04 stops the enzymes from protecting Tat, thereby allowing the cell to destroy Tat and along with it destroy the virus’ ability to “rev up.”

There is 1 key problem—JIB-04 itself is too toxic to serve as a standalone therapy for HIV. Katherine Jones, PhD, a professor in the Salk Institute’s Regulatory Biology Laboratory, however, said it nonetheless points the way to a number of other potential therapeutic avenues.

“We don't know whether JIB-04 could be modified in a way that would prevent toxicity to primary T cells,” she told MD Magazine, “but it certainly could be a useful lead compound for scientists to define the chemical features that are responsible for inhibiting Tat expression and study the mechanism of cell toxicity.”

In order to verify the method by which JIB-04 works, the researchers relied on a technique called differential precipitation of proteins, of DiffPOP, which enabled the team to better understand the drug/protein interactions at play.

For patients, the discovery could mark another important step forward in the quest to cure HIV. The virus can already be rendered something akin to a “chronic condition” via the use of antiretroviral therapy (ART), which can suppress the virus. The US Centers for Disease Control and Prevention, along with a number of international entities, has stated that once the virus is suppressed to the point of undetectability, it is also untransmittable.

However, daily ART therapy is costly and burdensome to patients, and if a patient were to stop taking the therapy, they would still face the risk of viral rebound.

Jones said attacking Tat could provide the way to a more durable suppression of the virus.

“There are reports that inhibition of Tat with other compounds is sufficient to give rise to a ‘functional cure,’ meaning that combination treatments with existing HAART therapy (highly active ART) and anti-Tat therapy might allow patients to go off of therapy without risking virus recurrence,” she said. “The existing studies are preliminary and have yet to be explored more rigorously comparing different compounds side-by-side and testing other mechanisms to inhibit Tat, but overall, this is a highly promising area of research.”

Jones and colleagues’ study is titled “SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation and destruction by autophagy.” It was published last month in PLOS Pathogens.

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