Scientists have for the first time built a detailed molecular model of the complex structure of the inner protein shell of HIV, paving way for potential new treatments for the deadly virus.
A team led by researchers at the University of Pittsburgh School of Medicine described the 4-million-atom structure of the HIV's capsid, or protein shell.
The findings, published in the journal Nature, could lead to new ways of fending off an often-changing virus that has been very hard to conquer.
Scientists have long struggled to decipher how the HIV capsid shell is chemically put together, said senior author Peijun Zhang, associate professor at the University of Pittsburgh School of Medicine.
"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," she said.
"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," said Zhang.
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, taking data from cryo-electron microscopy at an 8-angstrom resolution 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 said.
"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," Zhang said.
