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Scientists in the Scripps Research Institute (TSRI) and Weill Cornell Medical College have completed a brand new analysis of a key AIDS protein long regarded as one of the most difficult targets in structural biology, and their jobs are an essential step forward in the growth and development of an HIV vaccine.
In two separate papers published Thursday in Science Express, the online early edition of the journal Science, the researchers are convinced that they’ve determined the very first atomic-level structure of the tripartite HIV envelope protein.
Their findings provide the most detailed picture yet from the virus’s complex envelope, including sites that may be mimicked by future vaccines to produce an immune response. Currently, antiviral medicine is getting used to treat the roughly 34 million HIV-infected people worldwide, however the medical community’s attempts to create a vaccine to avoid infections and perhaps even eradicate the illness have fallen short up to now.
The biggest obstacle to some vaccine is Env, a name given to HIV’s envelope protein by virologists, the research authors explain. This protein’s structure is really delicate and sophisticated that researchers have had trouble acquiring the protein in a form that’s suitable to undergo atomic-resolution imaging.
“It has a tendency to break apart, for instance, even if it’s on the surface of the virus, so to study it we must engineer it to be more stable,” explained Andrew Ward, an assistant professor in TSRI’s Department of Integrative Structural and Computational Biology. Thus, the aim is to engineer a version of the Env trimer stable enough to become analyzed while keeping almost all of the original structural characteristics.
Ward, along with Ian A. Wilson, Bridget Carragher and other colleagues from TSRI, as well as John Moore, Rogier W. Sanders and other experts from Weill Cornell, successfully were able to create a form of the protein that can survive atomic-level imaging work while including all the trimer structure that normally sits outside of the viral membrane.
They then evaluated this new type of Env, dubbed BG505 SOSIP.664 gp140, using both X-ray crystallography and electron microscopy. The X-ray crystallography study marked the very first time that the imaging technique had been used to analyze Env, while each method resolved the trimer structure to a finer degree of detail than has been reported before, the authors of the two research papers said.
“The new data are consistent with the findings on Env subunits during the last Fifteen years, but also have enabled us to explain many prior observations about HIV in structural terms for the first time,” explained Dr. Jean-Philippe Julien, a senior research associate within the Wilson’s laboratory and first author from the X-ray crystallography study.
“Arguably the most crucial implications of the new findings are for HIV vaccine design,” Weill Cornell reported inside a statement. “In both of the new studies, Env trimers were imaged while certain to broadly neutralizing antibodies against HIV. Such antibodies, isolated from naturally infected patients, are the very rare ones that somehow bind to Env in a manner that blocks the infectivity of the high proportion of HIV strains.”
Under ideal circumstances, an HIV vaccine would result in a tremendous discharge of these kinds of the vaccine would take advantage of understanding the exact structural detail of the sites where the antibodies bind to the virus to enable them to be mimicked. The authors asserted the data they gathered is already being used towards vaccine development.
“We yet others are already injecting the trimer into animals to elicit antibodies,” Dr. Ward said. “We can look at the antibodies which are generated and if necessary customize the Env trimer structure and try again. Within this iterative way, we try to refine and boost the antibody response in the animals and eventually, humans.”
