There was an article in the Wall Street Journal earlier this month about scientists using a branch of mathematics known as random matrix theory to identify a part of the HIV genome that rarely undergoes mutation. This region encodes the protein responsible for forming a capsid that encapsulates many of the components of the virus (the capsid protein). Because this region of the genome rarely mutates, the resulting protein is an ideal target for drugs and vaccines.
I don’t presume to know anything about random matrix theory, and the fact that this region of the genome is highly conserved has actually been known for some time, but it is useful to see the target validated by other branches of science. The HIV capsid protein is capable of self-assembling to form a hexamer (requiring six units); each end of the hexamer is capable of assembling with other hexamers. Even though the individual interaction is very weak, the fact that the proteins can all “interlock” allows them to form a beautiful “honeycomb-like” network that keeps all of the virus parts together. All of this comes from many copies of a single protein.
This strategy allows HIV to minimize the size of its genome so that it can create the bare amount of components to survive. But the same strategy that allows the virus to create this network also has a vulnerability – a drug that is able to disrupt the interactions between the proteins can completely prevent the network from forming. Studies show that an HIV that is denied the ability to properly form the network from single point mutations has greatly reduced infectivity. This is the benefit and downfall of cooperativity: you can build seemingly impossible “superstructures” from relatively simple components, but if something were to happen to the interaction between the components, you’re in trouble.
The new advance in the fight against HIV has a special place in my heart because I proposed this as a target for my independent research proposal during my graduate training. It is a way to corner the virus: if it tries to mutate, it can’t form the network; if it doesn’t, it is vulnerable to the drug or vaccine. I suspect that the road remains long and difficult for scientists; it is not an easy protein surface to recognize, and, as one of my professors on my advisory committee criticized, once the network is formed it may be “locked” in place, making the binding site difficult to access. Thus, this strategy may require attacking the target early in the HIV formation process.
To see a visual representation of the hexamer network, visit the WSJ article. It can be found here.
The PNAS article can be found here.
