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New HIV drug hits virus in unexpected way

Staff Writer |
A new type of HIV drug currently being tested works in an unusual way, scientists in the Molecular Medicine Partnership Unit, a collaboration between EMBL and Heidelberg University Hospital, have found.

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They also discovered that when the virus became resistant to early versions of these drugs, it did not do so by blocking or preventing their effects, but rather by circumventing them. The study presents the most detailed view yet of part of the immature form of HIV.

HIV, the virus that causes AIDS, comes in two forms: immature and mature. The immature form is assembled inside an infected person's cells. After an immature virus particle has left the cell, it has to change into the mature form before it can infect other human cells.

A new group of drugs that inhibit this maturation is currently undergoing clinical trials, but so far it was unclear how exactly these drugs act.

To go from immature to mature, HIV has to cut the connections between its main building blocks, and rearrange those pieces. John Briggs' lab at EMBL and Hans-Georg Kräusslich's lab at Heidelberg University Hospital looked at a particularly important cutting point.

It connects building blocks known as the capsid protein and the spacer peptide 1, and if it is not cut, the virus cannot mature.

The scientists used a combination of cryo-electron tomography and subtomogram averaging to reveal exactly what this part of the immature form of HIV looks like in 3D. They found that the cutting site is hidden in a position where the virus' cutting machinery can't sever it. So for the virus to mature, the structure first has to change, to expose that cutting point.

"When we looked at the virus with one of these inhibitor drugs on it, we found that the inhibitor doesn't prevent the cutting machinery from getting in, as you might expect," says Florian Schur, who carried out the work in Briggs' lab. "Rather, the drug locks the immature virus structure in place, so that it can't be cut."

When the new inhibitor drugs were first developed, scientists found that HIV viruses with certain mutations in their genetic sequence were unaffected by the drugs - they were resistant.

Having determined what the cutting point looks like and how the drugs act, Briggs and colleagues are now able to understand the effects of those mutations.

"Rather than stopping the drug from binding, the virus becomes resistant through mutations that destabilise the immature structure," says Kräusslich. "This allows it to rearrange and be cut even when the drug is in place."

The researchers would now like to probe the virus and the inhibitor drugs in even greater detail, to understand exactly how the drugs attach themselves to the viral proteins, and potentially gather data that could help to search for better drugs - or to design them.

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