Researchers in Heidelberg have discovered how new HIV drugs can lock the virus into its immature phase, information vital to future drug design.
The scientists in the Molecular Medicine Partnership Unit, a collaboration between the Heidelberg branch of the European Molecular Biology Laboratory (EMBL) and Heidelberg University Hospital, discovered that when the human immunodeficiency virus (HIV) became resistant to early versions of these drugs, it did not do so by blocking or preventing their effects, but rather by circumventing them.
Heidelberg is a leading knowledge hub in HIV research as home to both the Briggs group at the EMBL, Europe’s flagship laboratory for the life sciences, and the Kräusslich research group within Heidelberg University Hospital’s Department of Virology. The former develops and applies cryo-electron microscopy techniques to study viruses such as HIV, while the latter’s research projects focus exclusively on different aspects of HIV biology. The German city is renowned for its intellectual capital in the field of molecular life sciences, and in June was host to the EMBL conference CTLS 2016 – Core Technologies for Life Science.
The immature form of HIV, the virus that causes AIDS, has to change into the mature form before it can infect other human cells. 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 used a combination of cryo-electron tomography and subtomogram averaging to reveal what the immature form of HIV looks like in 3D, focusing in on a particularly important cutting point which connects building blocks known as the capsid protein and the spacer peptide 1. If it is not cut, the virus cannot mature. They found that the cutting site is hidden in a position where the virus’s cutting machinery can’t sever it. So for the virus to mature, the structure first has to change, to expose that cutting point.
Florian Schur, who carried out the work in Briggs’ lab, said: “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. Rather, the drug locks the immature virus structure in place, so that it can’t be cut.”
Researchers are now able to understand why HIV viruses with certain mutations in their genetic sequence are resistant to inhibitor drugs. “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 now hope to probe the virus and the inhibitor drugs in greater detail, to potentially gather data that could help to create better drugs.
For HIV to mature, a crucial cutting point has to be exposed. (Credit: Florian Schur/EMBL)
(via EMBL and EurekAlert)