Pitt study outlines new way to tackle HIV

"This study unravels another molecule derived from the virus that can be targeted to inhibit replication of the virus," Kamel Khalili, chair of the microbiology, immunology and inflammation at Temple University's Lewis Katz School of Medicine, said via email statement. Khalili studies HIV but was not involved in this research.

"It is important to note that this strategy is not set up for elimination of the virus, but rather the decrease of viral replication," he noted.

Before PROTACs, the team screened over 250,000 compounds to identify preexisting nef inhibitors, which alone took 18 months and led to a previous paper by Emert-Sedlak.

The lab still wants to learn more about how to effectively destroy nef and plans to scale up to an animal model. They also want to examine any off-target effects of the PROTAC complex — in other words, changes to cells or side effects that are unintended.

While they showed that their PROTAC complex can destroy nef, they have more work to do to link it to full HIV clearance — and before they could link it to a viable treatment.

"We show that you can create molecules that go into cells, hit their target, seemed to destroy it, restore receptors, and have antiretroviral activity," said Smithgall. "But we haven't directly shown that, as a consequence, that will trigger an anti-HIV immune response. And we're actually doing that with another lab here. We're just starting those experiments."

And the team recognizes the need to address the potential of drug resistance, as often occurs with viral treatments.

"This is a huge problem, and it can't be ignored," said Smithgall. "How that is going to play out with nef isn't clear."

Thus far, it's one of the first studies that outlines using a PROTAC complex for infectious disease. PROTACs exist for cancer: The idea is to clear out the proteins that are allowing the bad guys to hide, enabling the immune system to fight back.

"Many viruses have nef-like proteins," said Emert-Sedlak — including the SARS-CoV-2 virus, which causes COVID-19. "This technology could be broadly applicable to other viruses."

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