An exciting new prospect for treating and preventing HIV infection involves using unusually powerful antibodies that target many different strains of the virus.
But two new studies suggest these so-called "broadly neutralizing antibodies" won't be a simple remedy. While an antibody named VRC01 was safe and well-tolerated in the studies, it was only briefly effective at suppressing the AIDS virus in 24 patients taken off standard anti-viral drugs. All of the patients' HIV rebounded by or before 8 weeks.
One of the studies was conducted by the University of Pennsylvania and the University of Alabama at Birmingham, while the other was done by scientists from the National Institutes of Health.
The researchers say the results, published this week in the New England Journal of Medicine, indicate that combinations of neutralizing antibodies may be needed for long term control of the virus. In the same way, the developers of early anti-viral drugs discovered they had to attack the microbe in several different ways to keep it from developing resistance and roaring back.
"We found a surprising amount of resistance," said Katharine Bar, a Penn AIDS researcher who led the trial of 14 patients. "What we found was that they had pre-existing virus that was resistant to VRCO1 -- and virus that developed resistance" to the antibody during treatment.
Antibodies are an important immune system defense against infection, but most antibodies that target HIV ward off only one strain, making them no match for the constantly mutating virus.
And because antiviral drugs suppress HIV replication without eradicating it, virus that hides out in the body rebounds within days of stopping the drugs.
However, over the decades of the AIDS epidemic, researchers recognized that a small, elite group of HIV-positive patients had unusually potent antibodies because they remained healthy for many years without taking antiviral drugs.
The first such super-antibody, VRC01, was isolated just six years ago by the NIH's Vaccine Research Center. The antibody was able to stop more than 90 percent of known HIV strains from infecting human cells -- at least, in lab dishes. Nearly 100 other broadly neutralizing antibodies have since been found, and advances in technology have made it possible to manufacture them in the lab.
VRC01 is one of the first to be made in sufficient quantities for human testing. It is being used in the Antibody Mediated Prevention study, the first trial to see whether antibodies can prevent HIV infection in high-risk groups. The NIH and two international HIV trials networks launched the study in April at sites including Philadelphia.
Neutralizing antibodies are "an exploding area, both for prevention and therapeutics," said Penn AIDS researcher Pablo Tebas, a senior author of the just-published study.
Because VRC01 had been shown to be so potent, patients in the new studies were not screened before enrollment to see if they were starting out with strains that could beat the antibody. After VRC01 was unable to keep the virus suppressed, analysis of stored blood samples showed that patients with the shortest times to HIV rebound harbored many viruses that were invulnerable to the antibody from the beginning.
"Future clinical trials may consider prescreening for resistance, although this is a complex task," the researchers wrote.
Despite the challenges, Tebas said the fact that VRC01 did keep the virus at bay, at least for awhile, opens the door to harnessing the immune system to fight a virus bent on destroying that system.
"I tend to be optimistic," he said. "I see the glass as half full. The next step is to use [antibodies] in combination -- maybe two or three or more."