Researchers at and associated with The Scripps Research
Institute, the International AIDS Vaccine Initiative (IAVI), and the
biotechnology companies Theraclone Sciences and Monogram Biosciences have
discovered two powerful new antibodies to HIV that reveal what may be an Achilles'
heel on the virus.
The researchers, led by Dennis Burton, a Scripps Research
professor and scientific director of the IAVI Neutralizing
Antibody Center
at Scripps Research, published their work on Thursday, September 3, 2009, in
Science Express, an advance, online issue of the journal Science. Researchers
will now try to exploit the newfound vulnerability on the virus to craft novel
approaches to designing an AIDS vaccine.
Two newly discovered broadly neutralizing antibodies, called PG9 and PG16, are the first to have been identified in more than a decade. Here, neutralizing antibodies (red) are shown heading toward the viral spike (blue), where they will target conserved regions on two loops (yellow and green). Image by Christina Corbaci and Rob Pejchal.
"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," said Wayne
Koff, senior vice president of research and development at IAVI. "And
having identified this one, we're set up to find more, which should further
accelerate global efforts in AIDS vaccine development."
Broadly neutralizing antibodies to HIV are produced by a
minority of HIV-infected individuals and are distinct from other antibodies to
HIV in that they neutralize a high percentage of the many types of HIV in
circulation worldwide. It is widely believed that to prevent HIV infection an
AIDS vaccine would need to teach the body to produce these powerful antibodies
before exposure to the virus. Animal experiments suggest that such a vaccine
would work. Before this finding only four antibodies to HIV had been discovered
that were widely agreed to be broadly neutralizing.
The two newly discovered broadly neutralizing antibodies,
called PG9 and PG16, are the first to have been identified in more than a
decade and are the first to have been isolated from donors in developing
countries, where the majority of new HIV infections occur. Moreover, previously
identified broadly neutralizing antibodies against HIV have functioned by
binding to places on HIV that have proven difficult to exploit by means of
vaccine design.
"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," said Burton, who is also a member of the newly established Ragon
Institute of Massachusetts General Hospital, Massachusetts Institute of
Technology, and Harvard University. "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."
Breadth of neutralization is important because any effective
AIDS vaccine must provide protection from a diverse range of the most prevalent
types of HIV circulating worldwide. High potency suggests that such antibodies
will not have to be produced by the body in very large quantities to confer
protection.
The two new antibodies target a region of the viral spike
used by HIV to infect cells. The viral spike glycoproteins, termed gp120 and
gp41, are highly variable and have evolved to thwart immune attack. But
biochemical studies suggest that PG9 and PG16 target regions of gp120 that do
not change, which probably accounts for their breadth of neutralization. Now
researchers at the IAVI-organized Neutralizing Antibody Consortium (NAC), a
scientific network focused on designing vaccines capable of eliciting broadly
neutralizing antibodies, will turn their attention to studying the molecular
structure of PG9 and PG16 and that of the region they target on the HIV spike.
They will use this information to try to devise immunogens—the active
ingredients of vaccines—that elicit similar antibodies.
How they were discovered
The methods by which PG9 and PG16 were isolated are
themselves proving instructive. Their identification represents the first
success of an ongoing global hunt launched by IAVI in 2006 to find new broadly
neutralizing antibodies to support the rational design of novel AIDS vaccine
candidates. The effort, named Protocol G, is unprecedented in scale and
distinguished by its emphasis on identifying antibodies that neutralize
subtypes of HIV circulating primarily in developing countries. IAVI's clinical
research partners have collected blood specimens from upward of 1,800
HIV-infected volunteers from IAVI-supported clinical research centers in seven
sub-Saharan countries as well as from centers in Thailand, Australia, the
United Kingdom, and the United States.
All samples were sent to Monogram Biosciences, which,
working with researchers at IAVI's AIDS Vaccine Design and Development
Laboratory in New York City and the IAVI Neutralizing Antibody Center at
Scripps Research, screened the sera for broadly neutralizing activity. Researchers
historically have sought broadly neutralizing antibodies in serum by testing
whether antibodies from such samples bind to soluble versions of gp120 and
gp41. It turns out that PG9 and PG16, however, bind to soluble forms of the
proteins very weakly, if at all. The antibodies were detected only because a
micro-neutralization assay developed by Monogram in partnership with IAVI
measuring their ability to block HIV infection of target cells was run in
parallel with the standard binding assays used for screening. This has
significant implications for the future screening of broadly neutralizing
antibodies.
"If you think of it as a fishing expedition," said
Christos Petropoulos, chief scientific officer and vice president of virology
research and development at Monogram Biosciences, "we and the rest of the
field were previously using the wrong bait in the search for HIV-specific
broadly neutralizing antibodies. Together with colleagues at IAVI, we reasoned
that the best approach to identifying antibodies with the most potent and broad
neutralizing activity was to screen directly for their ability to block HIV
infection. To do this we developed a new, specialized test known as the
micro-neutralization assay, which has opened up new avenues for exploration of
additional donors for similar antibodies."
Once the researchers had ranked the top 10 percent of serum
samples in terms of breadth of neutralization, they needed to isolate the
actual broadly neutralizing antibodies. This can be painstaking work. But Theraclone
Sciences, a company that had been working outside the HIV field, had a relevant
and unique high-throughput process that it adapted to HIV work with financing
from IAVI's Innovation Fund, which is co-funded by the Bill & Melinda Gates
Foundation. The Theraclone team used a system designed to expose the entire
repertoire of antibodies from a blood sample obtained from an HIV-infected
individual. Antibodies with broadly neutralizing potential were identified from
this pool and traced to their corresponding antibody-forming cells. Using
recombinant DNA technology, broadly neutralizing antibody genes were then
isolated from these cells to enable the production of unlimited quantities of
the antibody clones for research.
"It is exciting that we were able to use our technology
to identify and isolate these new broadly neutralizing antibodies, which may
offer important clues that could help create an effective AIDS vaccine. Through
this strong scientific partnership, we have rapidly delivered promising results,"
said Matthew Moyle, chief scientific officer and senior vice president of
Theraclone Sciences. "This project has been a useful demonstration of
Theraclone's antibody discovery platform in infectious disease, and we highly
value IAVI's collaborative approach to solving the AIDS vaccine
challenge," said David Fanning, president and CEO of Theraclone
Sciences.
With a large pool of HIV-positive donors from Protocol G now
identified whose serum contains HIV-specific broadly neutralizing antibodies,
it is likely that this global collaboration will generate more broadly
neutralizing antibodies that will benefit the vital enterprise of accelerating
AIDS vaccine development.
"The story of the discovery of these two new antibodies
demonstrates the challenges of AIDS vaccine research but also the power of the
collaboration that formed to produce this advance. This is what can happen when
you have researchers from the global North and South, from academia and
industry, from within and outside the HIV field, working together in a
framework to speed innovation," said Seth Berkley, president and CEO of
IAVI. "By working in this manner, I am confident we will continue to move
toward solving the AIDS vaccine challenge, one of the greatest scientific and
public health challenges of our time."
"Broad and
Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine
Target"
This work was supported by IAVI, IAVI's Innovation Fund
(cofunded by IAVI and the Bill & Melinda Gates Foundation), the United
States Agency for International Development (USAID), and the National Institute
of Allergy and Infectious Diseases of the National Institutes of Health.
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