HIV cell puncturing pathway changes conventional wisdom

Two theoretical physicists have uncovered what they believe is the long-sought-after pathway that HIV takes to enter healthy cells. They hope the discovery could help scientists treat other human illnesses by exploiting the same molecules that make HIV so deadly.

Computer image of cell membrane being pierced by HIV peptides

The theorists from the Rensselaer Polytechnic Institute in the US analysed biocomputation and simulation to uncover a surprisingly simple mechanism describing how a HIV protein fragment penetrates the cell membrane.

“What we saw in our computer calculations wasn’t at all what we expected to see when we began,” said Senior Constellation Professor of Biocomputation and Bioinformatics Angel Garcia. “The mechanism for entrance in the cell was clear in one simulation, but in some instances simulations show one result and you never see that result again. Then we started doing other simulations and it kept happening again and again.”

For the last decade, scientists have known that a positively charged, 11-amino-acid chain of HIV (HIV-1 Tat protein) can do the nearly unthinkable - cross through the cell membrane. Sometimes referred to as an “arrow protein,” HIV-1 Tat pierces the cell membrane and carries a cargo though the cell membrane.
Its unique cell-puncturing ability has been the subject of hundreds of scientific articles investigating the type of materials that can piggyback on the peptide and also enter the cell. Researchers have proposed using the peptide to deliver genes for gene therapy and drugs that need to be delivered directly to a cell. But despite many potential medical applications, the actual mechanism that opens the holes in the cell remained undiscovered.

The Rensselaer researchers have discovered that the positively charged HIV peptide is drawn to negatively charged groups inside the cell membrane. When the HIV peptide cannot satisfy itself with the negative charges available on the cell membrane surface it is directly attached to, it reaches through the membrane to grab negatively charged groups in the molecules on the other side, opening a transient hole in the cell.

“The peptide entered the forbidden territory of the cell,” Garcia said. “This is when this mechanism starts to challenge conventional wisdom.”
The findings are detailed in the Proceedings of the National Academy of Sciences (PNAS).