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Saturday, September 5, 2009

Discovery Of New HIV Antibodies Opens Door To Effective AIDS Vaccine

By examining blood samples donated by infected people in developing countries, US researchers have found two new powerful antibodies to HIV that open the door to a new and effective AIDS vaccine. The antibodies, called PG9 and PG16, are of a type known as bNAbs (broadly neutralizing antibodies) and exploit an "Achilles heel" or vulnerable spot in the HIV that could be an effective target for a vaccine, said the researchers.

The discovery was made by researchers working at and with the International AIDS Vaccine Initiative (IAVI), at The Scripps Research Institute, and at the biotechnology companies Theraclone Sciences and Monogram Biosciences, and was published on 3 September as an online advanced issue in Science.

Co-principal investigator Wayne Koff, who is senior vice president of research and development at IAVI in New York, told the media:

"The findings themselves are an exciting advance toward the goal of an effective AIDS vaccine because now we've got a new, potentially better target on HIV to focus our efforts for vaccine design."

He said now they've found this target they can look for more, and speed up global efforts to develop an effective AIDS vaccine.

The discovery relied on a global collaboration that developed a new way of looking for bNAbs, and the researchers fully expect more to be found, revealing further vulnerable spots on HIV for vaccines to target.

Only a small proportion of people infected with HIV produce bNAbs, a range of antibodies that are different to other antibodies because they effectively neutralize a high proportion of the HIV types in circulation around the world.

Animal experiments suggest that if the body can "learn" to produce these types of antibody, which is what an effective AIDS vaccine induces, then it is able to protect itself from infection by HIV.

Other bNAbs against HIV have been discovered before, but PG9 and PG16 are the first to be isolated in over 10 years from donors in developing countries, where most new HIV infections occur. Also, the previously identified bNAbs bind to spots on the virus that are hard to target with vaccines.

One of the other co-principal investigators, Dennis Burton, who is professor of immunology and microbial science and scientific director of the IAVI Neutralizing Antibody Center at The Scripps Research Institute in La Jolla, California, said:

"These new antibodies, which are more potent than other antibodies described to date while maintaining great breadth, attach to a novel, and potentially more accessible site on HIV to facilitate vaccine design."

"So now we may have a better chance of designing a vaccine that will elicit such broadly neutralizing antibodies, which we think are key to successful vaccine development," added Burton, who is also a member of the newly established Ragon Institute of MGH, MIT and Harvard.

For a vaccine to be effective it must be able to stimulate the immune system to make broad spectrum antibodies that can effectively neutralize as many forms of the virus as possible. Ability to stimulate high potency antibodies also makes it more likely that the vaccine does not need to stimulate production of too many antibodies to make it effective.

One of the features of HIV that gives it an advantage, is a viral "spike" that it uses to invade cells. The "spike" foils attack by the immune system because it relies on two glycoproteins, gp120 and gp41, which keep changing. This is a successful tactic for HIV because by the time the immune system has noticed the new version of the spike and made new antibodies to attack it, the virus has invaded enough host cells to allow it to replicate in large numbers and overwhelm the immune system.

But PG9 and PG16 attack a part of the "viral spike" of the HIV: specifically they attack regions of gp120 that don't change, and this is probably why they are broad spectrum neutralizers.

There are probably two main reasons why the researchers were able to discover PG9 and PG16: one was the high number of blood samples they were able to access from a range of developing countries, and the other was they used a new way of testing whether bNAbs bind to gp120 and gp41.

The blood samples the researchers used were donated by HIV-infected volunteers from IAVI-supported clinical research centers based in seven sub-Saharan countries as well as in Thailand, Australia, the UK and the US.

The conventional way of testing the ability of bNAbs to bind to gp120 and gp41 uses soluble forms of the proteins, and if Koff, Burton and colleagues had used it they would probably have rejected PG9 and PG16 as candidate bNAbs because they bind weakly to soluble forms of the proteins. But they used a new method that relies on a micro-neutralization assay developed jointly by Monogram Biosciences and IAVI which they ran in parallel with the standard binding assays.

This new method is likely to make a significant difference to the way bNAbs are screened in the future, because it allows researchers to screen bNAbs directly for their ability to block HIV infection.

Another important aspect of the work was the contribution of Theraclone Sciences, a company that was initially working outside of the HIV field, but they had a relevant and unique high throughput process that could be adapted to isolate the effective bNAbs in a much shorter time. Funding from IAVI's Innovation Fund, which is co-funded by the Bill & Melinda Gates Foundation helped to pay for the adaptation.

The process that the Theraclone team used exposes all the antibodies in a blood sample from an HIV infected person, identifies those with broadly neutralizing potential and traces them to their corresponding antibody-forming cells. With recombinant DNA technology, they isolated genes from the candidate bNAbs so they could clone them in large numbers for testing.

Chief scientific officer and senior vice president of Theraclone Sciences, Matthew Moyle, said:

"It is exciting that we were able to use our technology to identify and isolate these new bNAbs, which may offer important clues that could help create an effective AIDS vaccine."

Source: http://www.medicalnewstoday.com


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