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The threat of HIV has led to an enormous amount of information on virus infection in general,
and in particular on the architecture of the HIV virus and of the various steps that it
undergoes in living cells.
There are several therapies that have been developed over the years against HIV.
The problem with those therapies is that for every single therapy that was developed, the HIV
became immune to that therapy. So that is why people have to go to from one drug to
another when they are infected with HIV.
A virus that infects a cell contains, at the core of it, genetic material it tries to smuggle
into the cell. And this genetic material is packaged in what is called the capsid.
That capsid is a very strong container for this genetic material, to protect it as long as
the virus is outside of the cell. But once the virus enters the cell and has infected
the cell, then the capsid has to be a very quickly opening container on the other side.
If you want to chemically attack the capsid for medical reasons, then you need to know
the full chemical detail of the capsid. And that was not available when the project started.
So before that we knew it was a polymorphic structure. So we knew that two of them are
going to be different. Then we knew the building blocks. So we knew that it was made of pentamers
and hexamers. But all that information was known of isolated parts. We did not have the
whole structure together. In experiments we have different techniques that can look at
the same thing at different size scales and at different resolutions. You can look at
great detail. And you can look in the physiological conditions of the proteins. But you can only
look at really small pieces of them. You cannot look at the whole assembly.
Then the people who do electronmicroscopy, they can look at large assemblies at low resolutions.
But you cannot see what each atom is doing. So we have to find a way of putting all of
this together to build the capsid.
We taught our computer program, over many decades, how to simulate the macromolecules
of the living cell. And so now ,what the computer can do is, it can try to take the pictures
of the individual proteins that you see very clearly, and match them into these fuzzy images
of the proteins that appear with the electronmicroscope.
So what we do is computational modeling. If you look at what we do, it might look like
a video game. But we actuallyâ what is going on there is real. It is what you will see
if you were able to look through a microscope at that scale. Essentially what we do is solve
Newton's equations of motion for the system. But we do this for several thousands of atoms
and how they are interacting and we solve these for several microseconds.
The capsid is made actually out of over a thousand proteins. All together, we had to
simulate the system of three million atoms that made the envelope and, in addition, all
the liquid and salt ions, liquid molecules, water molecules. That gave us, all together,
64 million atoms. And this was, absolutely by far, a simulation that was never done earlier.
But we were very, very fortunate because, right when this project was developing, the
University of Illinois got delivery of the Blue Waters computer.
So Blue Waters is larger, faster... I mean it was essential to the success of the project.
Because it is the only machine where we could have run a simulation of this size.
So we now we had one of the fastest and largest computers in the world available. And we knew
on this computer you could simulate an up to 100 million atom systems. And so 64 million
fit it actually snugly into the computer. And so we could carry out the necessary simulation.
And so we did.
We simulated 64 million atoms. It took us a month.
And I will not forget the day that he came running to me and said,
"Klaus! Klaus! Look at it. Look at it. How beautiful."
And, in fact, it was really, like many important scientific results are,
they are just initially and immediately beautiful and clear. And so we got here a
very lucky outcome of a very difficult computer simulation. And we could now look, protein
by protein, how these, over a thousand proteins, are capable of realizing a rather wide distribution
of local shapes along the surface of the HIV capsid. And so that gave us, for the first
time, the details of the astonishing maliability of the capsid proteins.
Some of our findings are actually key because you can do a single mutation and you rendered
the virus inactive. That means you know in very small details, you know what is going
to happen at large scale.
It also gave us first insight into how one might approach this capsid through pharmacological
warfare by developing drugs that might fit into some of the nooks and crannies and thereby
shut the capsid so that it could not release its genetic content when it was actually infecting a cell.
The capsid is really attractive because it is essential to the survival of the virus.
But also it is because... like in monkeys, monkeys are immune to HIV. And the way they
are immune to HIV is by attacking the capsid. They destroy the capsid once it gets into
their cells. So the reason we have never developed drugs against the HIV-1 capsid is because
we did not know what it looked like. So we essentially are giving, we are giving to the
world this capsid that is the platform for the development of new therapies.
And that is why it is so important.
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