by Mike Andrew - SGN Staff Writer

Researchers from the University of Pittsburgh School of Medicine, the University of Illinois, Vanderbilt University, and the University of Central Florida have mapped for the first time the structure of the protein shell surrounding the HIV virus. Their findings are published in the current issue of Nature.

The virus's protein shell, called the 'capsid,' sits inside the outer membrane of the virus, and is made up of a complex lattice of protein molecules, including about four million atoms.

'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,' said study leader Dr. Peijun Zhang, an associate professor at the University of Pittsburgh School of Medicine.

'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.'

Before the latest study, it was known that the HIV capsid is cone-shaped, but because it is asymmetrical and non-uniform, standard techniques for working out the structure had proved ineffective. The University of Pittsburgh team used advanced imaging techniques and a supercomputer to calculate how the 1,300 proteins that make up the capsid fit together.

EXCITING POSSIBILITIES
The process revealed critical interactions between molecules in areas that are necessary for the shell's assembly and stability. These potential vulnerabilities in the protective coat of the viral genome could be exploited by scientists designing new drugs to tackle the problem of HIV resistance, the researchers explained.

'Current HIV therapies work mostly by targeting certain enzymes, but bear drug resistance issues due to the virus' high mutation rate,' noted Zhang. 'This approach has the potential to be a powerful alternative to our current HIV therapies ...'

Professor Simon Lovell, a structural biologist at the University of Manchester, said that the researchers had found some 'really interesting' results that could have important practical applications.

'The big problem with HIV is that it evolves so quickly that any drug you use you get drug resistance, which is why we use a multi-drug cocktail.

'This is another target - another thing we can go after to develop a new class of drugs to work alongside the existing class.'

'By using a combination of experimental and computational approaches, this team of investigators has produced a clearer picture of the structure of HIV's protective covering,' National Institutes of Health program director Michael Sakalian said in a statement.

'The new structural details may reveal vulnerabilities that could be exploited by future therapeutics.'

NIH and the National Science Foundation funded the study.

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