Washington: Scientists have determined the structure of a key part of the HIV envelope protein, an advance that brings an HIV vaccine closer to reality. HIV virus has many strategies to hide from the immune system. One of those strategies is a dramatic structural transformation that the virus undergoes when it fuses to a host cell.
The envelope protein complex is a structure that protrudes from HIV's membrane and carries out the infection of healthy host cells. Scientists have long targeted this complex for vaccine development, specifically its three copies of a protein called gp41 and closely associated partner protein gp120. Researchers from Duke University said they think about a particular region of gp41, called MPER, as an Achilles' heel of vulnerability.
"The attractiveness of this region is that, number one, it is relatively conserved," said Leonard Spicer, senior author and a professor of biochemistry and radiology. In a virus as genetically variable as HIV, a successful vaccine must act on a region that will be conserved, or similar across subtypes of the virus.
"Second, this region has two particular sequences of amino acids that code for the binding of important broadly neutralising antibodies," said Spicer. The HIV envelope region near the virus membrane is the spot where some of the most effective antibodies found in HIV patients bind and disable the virus. When the virus fuses to a host cell, the HIV envelope protein transitions through at least three separate stages. Its pre- and post-fusion states are stable and have been well studied, but the intermediate step - when the protein actually makes contact with the host cell, is dynamic.
The instability of this interaction has made it very difficult to visualise using traditional structure
determination techniques, such as x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Duke researchers solved the structure using protein engineering, sophisticated NMR and software specifically designed to run on limited data. First author Patrick Reardon engineered a protein that incorporated the HIV MPER, associated with a membrane and behaved just like gp41 in the tricky intermediate step, but was stable enough to study. They captured the shape of the three-parted MPER in its near-native state, but the protein needed to be more than structurally accurate - it had to bind the broadly neutralising antibodies.
"One of the most important aspects of the project was ensuring that this construct interacted with the desirable antibodies, and indeed, it did so strongly," Reardon said. In December last year, the university received a grant of up to $2.9 million from the Bill & Melinda Gates Foundation to fund the development of an HIV vaccine that will build on these findings.
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