Pitt study outlines new way to tackle HIV

Is it a cure for HIV?

"We try to avoid the use of the c-word," joked Smithgall.

They accomplished their results with a little bit of chemistry Legos, if you will. The team took a compound called a nef-inhibitor — which binds to the nef protein, and which they had created and described in past research — and made it into a complex called a PROTAC, with a molecule that links them together.

PROTACS are large molecules that degrade proteins by attaching a "red flag" to them, thus directing them to the proteasome — what Emert-Sedlak refers to as the "garbage disposal of the cell."

That flag, in this case, is a protein called ubiquitin, which the body already produces en masse (hence its name): "We're utilizing the cell's own machinery," said Emert-Sedlak, a Pittsburgh native who joined Smithgall's lab in 2005.

Ubiquitin is abundant. The task for the team was to create numerous different PROTACs in order to find ones that worked well.

So Colin Tice, a research fellow at the Philadelphia-area Fox Chase Chemical Diversity Center, synthesized more than 100 compounds for the team to test out. After months of experimentation, they settled on a dozen promising compounds.

The team grew human T cells in a dish — T cells are a kind of immune cell in the body — with nef, which had a fluorescent tag attached so researchers could see when it was produced. Then, after expressing nef, they fed the cells the dozen PROTACs and measured whether they degraded nef.

They found that a select six or seven PROTACs destroyed nef via flagging it for the aforementioned garbage disposal. The PROTACs also restored key cell surface proteins that are often dangerously low in people infected with HIV and help the body to recognize infected cells.

The entire study took more than two years to complete.

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