U. PITTSBURGH (US) — The first description of the 4-million-atom structure of the HIV’s capsid, or protein shell, could lead to new ways to fight the virus.
The findings are highlighted on the cover of the May 30 issue of Nature.
“The capsid is critically important for HIV replication, so knowing its structure in detail could lead us to new drugs that can treat or prevent the infection,” says senior author Peijun Zhang, associate professor of structural biology at the University of Pittsburgh School of Medicine. “This approach has the potential to be a powerful alternative to our current HIV therapies, which work by targeting certain enzymes, but drug resistance is an enormous challenge due to the virus’ high mutation rate.”
Three neighboring hexameric assembly units in the HIV capsid. (Credit: University of Pittsburgh)
Previous research has shown that the cone-shaped shell is composed of identical capsid proteins linked together in a complex lattice of about 200 hexamers and 12 pentamers, Zhang says.
But the shell is non-uniform and asymmetrical; uncertainty remained about the exact number of proteins involved and how the hexagons of six protein subunits and pentagons of five subunits are joined.
Standard structural biology methods to decipher the molecular architecture were insufficient because they rely on averaged data, collected on samples of pieces of the highly variable capsid to identify how these pieces tend to go together.
Instead, the team used a hybrid approach. They took data from cryo-electron microscopy at an 8-angstrom resolution (a hydrogen atom measures 0.25 angstrom) to uncover how the hexamers are connected, and cryo-electron tomography of native HIV-1 cores, isolated from virions, to join the pieces of the puzzle.
Collaborators at the University of Illinois then used their new Blue Waters supercomputer to run simulations at the petascale, involving 1 quadrillion operations per second, that positioned 1,300 proteins into a whole that reflected the capsid’s known physical and structural characteristics.
The process revealed a three-helix bundle with critical molecular interactions at the seams of the capsid, areas that are necessary for the shell’s assembly and stability, which represent vulnerabilities in the protective coat of the viral genome.
“The capsid is very sensitive to mutation, so if we can disrupt those interfaces, we could interfere with capsid function,” Zhang says. “The capsid has to remain intact to protect the HIV genome and get it into the human cell, but once inside it has to come apart to release its content so that the virus can replicate.
“Developing drugs that cause capsid dysfunction by preventing its assembly or disassembly might stop the virus from reproducing.”
The National Institutes of Health and the National Science Foundation funded the work. Researchers from Vanderbilt University School of Medicine and the University of Central Florida, in Orlando, collaborated on the project.
Source: University of Pittsburgh