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Patients Provide Clues to Producing a Powerful HIV Antibody

The key to creating an effective HIV vaccine may be found by mimicking the immune characteristics of people who produce a powerful type of antibody after being infected with the virus, suggests a new study published in the 29 July issue of Science Immunology, the latest addition to the Science family of journals.

Barton Haynes describes steps toward a HIV vaccine. | Shawn Rocco/ Duke Health

Researchers have now identified the immune system changes that occur over years in people who generate so-called broadly neutralizing antibodies (bnAbs) after being infected with HIV. The presence of these immune changes, though not yet known to directly trigger bnAbs production, consistently coincides with the creation of these powerful antibodies.

Antibodies are sniper-like proteins that mark harmful immune system intruders like viruses and bacteria for destruction. While antibodies are powerful weapons against an array of intruders, most are not strong enough to quell a viral attack by HIV. Broadly neutralizing antibodies can attack and disarm a wide variety of HIV viruses, but these powerful, pathogen-zapping proteins seldom occur naturally in HIV-infected individuals.

The immune changes seen in people who manufacture bnAbs, however, could help scientists figure out how to coax these antibodies into action in patients with HIV infection.

"This pathway is a blueprint for what we will have to recreate in order to induce bnAbs in the setting of vaccination," said Barton Haynes, a professor of medicine at the Duke Human Vaccine Institute. "Our hope is that we'll learn enough about the bnAb process to short-circuit the years and years of [immune system change] that the setting of natural infection requires in order to create bnAbs in a shorter period, for vaccines."

In the rare instance that HIV-infected individuals do produce bnAbs, the bnAbs neutralize only about 50% of HIV strains — not enough when the viruses have already damaged much of the hosts' immune systems. Producing the antibodies also takes years, at which point the antibodies do little to help the individuals who made them.

Thus, scientists across the globe have sought ways to encourage the quick and plentiful production of bnAbs, but so far, these efforts have failed.

Scientists are studying immune system differences in people who produce powerful antibodies against HIV. | AAAS/ Carla Schaffer

In a particularly large sample group of 239 infected individuals, Haynes and his colleagues aimed to uncover why these efforts have stalled. "Early on, when the first broadly neutralizing antibodies were isolated from infected individuals," said Haynes, "it became clear to us that they were unusual antibodies, with traits that looked like they came from people who had autoimmune disease, where the immune system acted back."

Taking cues from past analyses, which pointed to profound shifts in immune system function associated with bnAbs, the team compared the immune systems of two groups of HIV-infected individuals — one group with bnABs and the other without the antibodies.

Ultimately, they found that the first group had a unique set of immune characteristics — including a greater frequency of plasma autoantibodies — antibodies in the blood plasma that attack the body's own cells. "The presence of autoantibodies is … a signal that [immune] tolerance has been broken," explained Haynes. This is similar to what happens in people with autoimmune disorders, like rheumatoid arthritis or multiple sclerosis.

"By showcasing studies that span disciplines and technologies, Science Immunology will encourage collaborative and innovative research. Advised by an international group of forward-thinking researchers in immunology and beyond, Science’s newest journal will provide a broad platform for the most exciting findings in this growing field."

— Wrote Science Immunology Editor Angela C. Colmone, with Chief Scientific Advisors Abul K. Abbas, M.D. and Federica Sallusto in an editorial in the magazine's first edition.

People who could produce bnAbs also had many other traits widely associated with autoimmunity, such as a lower frequency of regulatory T-cells.

Haynes and his colleagues suggest that therapies that generate broadly neutralizing antibodies without including these complementary immune features will not be effective. His team recommends vaccines that set the stage for bnAbs production. The vaccines would provide the immune characteristics observed in people with bnAb-producing capabilities, and these immune changes, in turn, would encourage bnAb production. "All the work we are doing is in an effort to induce bnAbs [and] have them present before infection," said Haynes.

"We're continuing to study individuals who are HIV-infected and make the right kind of antibodies to understand as precisely as we can what happens when bnAbs are made," he added. "It's those series of events that are going to have to translate to what happens when a vaccine is administered in order to get the same types of protective responses."


Juwon Song

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