Anti-HIV drugs have prevented millions of early deaths from AIDS, but infected people must take the pills every day, for life. Now, two studies in small numbers of people show for the first time that infusions of two powerful anti-HIV antibodies can completely suppress the virus for several months. If the results pan out in larger studies, they could simplify treatment for people who have difficulty taking daily medication, reduce the risk of drug resistance emergence, and even help cut HIV transmission rates.
“This is a really exciting advance,” says Katharine Bar, a clinical virologist at the University of Pennsylvania who was not involved with the work. Bar is particularly heartened because she had conducted two similar studies with a single antibody that had little lasting impact: Resistant viruses quickly emerged. These failures, along with disappointing results in animal studies, led some in the field to think that the strategy had no merit.
Immunologist Michel Nussenzweig at The Rockefeller University in New York City wondered whether the antibodies needed more muscle. He and colleagues gave people infusions of two antibodies that had more wallop than Bar’s single antibody. As they show today in studies published in Nature and Nature Medicine, the strategy paid off in most people in two trials.
Nussenzweig and colleagues selected two antibodies that both have more power than the single one tested earlier and can “neutralize” a broader range of HIV variants. These so-called broadly neutralizing antibodies naturally emerge in some HIV-infected people who have had uncontrolled infections for several years, but at that point, the antibodies have little control over the infection. The study published in Nature tested three infusions of the antibodies on 11 people who had suppressed their infections with antiretroviral (ARV) drugs that cripple HIV and then stopped taking their medication. The Nature Medicine paper describes a trial involving seven people who were not on treatment and had relatively high levels of virus at the start.
In the first study, nine of the 11 people who stopped ARVs suppressed the virus to below standard tests’ detection levels for an average of 15 weeks before HIV rebounded. Analyses showed that the two people whose virus rebounded earliest had HIV variants that were resistant to both antibodies at the trial’s start. Intriguingly, two of the participants have remained off ARVs for a year without the virus rebounding.
The antibodies performed less well in people who began with high levels of virus, but four of the seven participants did suppress HIV for about 3 months. The people who did not respond to infusions again at the outset had viruses that dodged the antibodies. “Ultimately, this may not be good for everybody, and it’s expensive. But if you think about cancer, we’ve really made a big difference with immune therapies,” Nussenzweig says. “For HIV, there’s no such thing.”
Steven Deeks, who specializes in HIV cure research at the University of California, San Francisco, says he’s particularly curious about the two trial participants who are still off ARVs. He stresses that, for unexplained reasons, a small percentage of people stop ARVs and control their infections for years, and these two trial participants might just be part of that lucky group. Or it could be that the antibody treatment has something called a “vaccinal” effect that far outlasts the life of the antibodies.
Deeks points to an earlier monkey study with these antibodies that hinted at a vaccinal effect. In that experiment, led by virologist Malcolm Martin of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and co-authored by Nussenzweig, six animals infected with a monkey version of the AIDS virus controlled the infection for more than 2 years—far longer than the antibodies last. The researchers showed that the virus came roaring back when they depleted a type of T lymphocyte in the monkeys that helps the immune system eliminate HIV-infected cells.
This suggested to them that when the antibodies bound to the virus, the immune system developed strong T cell responses to them that persisted. In effect, the antibody treatment inadvertently offered long-term protection by goosing the immune system. “That’s the profile we’re all hoping to create in our patients right now, and this gives us a viable, testable strategy that could work in at least some people,” Deeks says.
Nussenzweig says much more work has to be done before antibody treatment of HIV infection proves its worth. In addition to improving the ability to see who is most likely to respond to the treatment, his group is modifying the antibodies so that they last longer in the body. Nussenzweig predicts he’ll soon have antibodies that retain function for nearly a year. “That’s a long, long time,” he says. Combination antibody studies with more patients are in the planning stages.
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