Powerful antibodies can completely suppress HIV for several months

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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 in the studies, 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 “neutralise” a broader range of HIV variants. These so-called broadly neutralising 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 first study 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 second 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 specialises 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.

Abstract 1
Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg−1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.

Authors
Pilar Mendoza, Henning Gruell, Lilian Nogueira, Joy A Pai, Allison L Butler, Katrina Millard, Clara Lehmann, Isabelle Suárez, Thiago Y Oliveira, Julio CC Lorenzi, Yehuda Z Cohen , Christoph Wyen, Tim Kümmerle, Theodora Karagounis, Ching-Lan Lu, Lisa Handl, Cecilia Unson-O’Brien, Roshni Patel, Carola Ruping, Maike Schlotz, Maggi Witmer-Pack, Irina Shimeliovich, Gisela Kremer, Eleonore Thomas, Kelly E Seaton, Jill Horowitz, Anthony P West Jr, Pamela J Bjorkman, Georgia D Tomaras, Roy M Gulick, Nico Pfeifer, Gerd Fätkenheuer, Michael S Seaman, Florian Klein, Marina Caskey, Michel C Nussenzweig

Abstract 2
Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7,8,9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10,11,12. Here we report on a phase 1b clinical trial (NCT02825797) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg−1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.

Authors
Yotam Bar-On, Henning Gruell, Till Schoofs, Joy A Pai, Lilian Nogueira, Allison L Butler, Katrina Millard, Clara Lehmann, Isabelle Suárez, Thiago Y. Oliveira, Theodora Karagounis, Yehuda Z Cohen, Christoph Wyen, Stefan Scholten, Lisa Handl, Shiraz Belblidia, Juan P Dizon, Jörg J Vehreschild, Maggi Witmer-Pack, Irina Shimeliovich, Kanika Jain, Kerstin Fiddike, Kelly E Seaton, Nicole L Yates, Jill Horowitz, Roy M Gulick, Nico Pfeifer, Georgia D Tomaras, Michael S Seaman, Gerd Fätkenheuer, Marina Caskey, Florian Klein, Michel C Nussenzweig

Sciencemag report
Nature abstract
Nature Medicine abstract


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