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Antibody treatment surprisingly ‘cures’ monkeys of HIV-like infection

Antibody treatment surprisingly ‘cures’ monkeys of HIV-like infection

hiv-cure“Fascinating.” “A complete first.” “Striking.” “Too amazing to be real.” Those are some of the reactions researchers are having to a provocative, baffling monkey study suggesting that a monoclonal antibody used to treat inflammatory bowel disease in humans might lead to a “functional” cure of an infection with the AIDS virus.

HIV therapies have improved to the point that combinations of antiretroviral (ARV) drugs routinely knock down the virus so effectively that standard tests cannot detect it in the blood. Researchers have long sought strategies that would allow people to stop taking their ARVs without the virus rebounding—a functional rather than complete cure, because patients would still harbor the virus, which integrates its genes into the DNA of a host’s cells. Yet save for a few notable exceptions, almost everyone who has stopped taking ARVs has seen the virus jump back to high levels a few weeks later. To keep the virus at bay, HIV-infected people must take ARVs for life.

In Science today, a team led by immunologist Aftab Ansari of Emory University School of Medicine in Atlanta describes infecting eight monkeys with SIV, the simian version of HIV, treating them with ARVs, and then infusing them with an antibody similar to an approved drug for Crohn’s disease and ulcerative colitis that targets a receptor on immune cell surfaces known as α4ß7. More than 9 months after the ARVs and antibody treatments were stopped, all eight animals had low or undetectable levels of SIV in their blood. In seven SIV-infected control animals that received what amounts to a placebo antibody, the virus rebounded to high levels within 2 weeks of stopping ARVs.

“The results knocked us out, they were so stunning,” says co-author Anthony Fauci, an immunologist who heads the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

Ansari stresses that animals treated with anti-α4ß7 remain infected. “They’re not cured—far from it,” Ansari says. Moreover, he and Fauci don’t know how the treatment works. “It has made us think 10 times over, ‘What the hell is going on in the system?'” Ansari says. “It’s really a puzzle.”

He, Fauci, and other AIDS researchers became interested in α4ß7 because it is found on the surface of CD4 cells, the immune cells that are the main target of HIV. The protein helps CD4 cells home in on the gut, where they gather in large numbers. Unfortunately, α4ß7 can also bind to HIV’s surface protein, which makes CD4 cells far more susceptible to infection and explains why the virus destroys those cells in the gut early in an infection. Ansari and Fauci were also tantalized by results from an earlier monkey study they conducted, which showed that the α4ß7 antibody could thwart infection with SIV. They proposed a straightforward mechanism for the protection: The antibody reduced the CD4 cells’ tendency to home in on the gut, providing fewer targets for any AIDS virus there.

Weirdly, the monkeys in the new experiment had higher levels of α4ß7-studded CD4 cells in their guts. And a novel positron emission tomography/computerized tomography scan that can show tagged viruses revealed that the animals treated with the anti-α4ß7 had higher levels of SIV than the control animals in some parts of the body, such as the small intestine. The treated monkeys did show signs of immune responses that might have helped them control SIV, but none was particularly strong.

“Everything they expected to happen didn’t happen, but what did happen was interesting,” says Steven Deeks, a clinician who conducts HIV cure studies at the University of California, San Francisco. “The immune system is unknowable, dynamic, complicated, and it always surprises you.”

Despite the lack of a clear-cut mechanism, immunologist Rafick-Pierre Sékaly at Case Western Reserve University in Cleveland, Ohio, predicts the apparent success will trigger a bevy of new studies. “That paper is going to orient the research in a completely new direction,” he says. Sharon Lewin, a leading HIV cure researcher at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, says the work “has very convincing data” and that it’s “a really impressive finding.” But Lewin adds a word of caution echoed by many, including the study authors: “Whether it’s a quirk of the monkey model, we don’t know,” she says.

It’s also possible that anti-α4ß7 worked because the experimental design tipped the scales toward success in a way that doesn’t reflect a typical HIV infection. For one thing, Ansari and Fauci’s team started the monkeys on ARVs 5 weeks after infection, which is far earlier than most people start treatment. Louis Picker, an immunologist who develops AIDS vaccines at Oregon Health & Science University, Beaverton, also wonders whether the SIV used might have been weakened, as his own experiments with the same strain have produced far higher peak levels of virus in the blood of untreated animals.

Picker suspects some undefined immune response explains the viral control. “What this experiment appears to be doing is nudging the viral/immune balance to the host rather than the virus,” he says. “I suspect if you took an antibody to CD4 and did the same experiment you’d see the same thing.”

But Picker allows that no other group has yet published similar results. And perhaps most important, unlike the CD4 monoclonal antibody, the one against α4ß7 has a human version, vedolizumab, already approved for clinical use. Indeed, NIAID began studies of it in HIV-infected people 3 weeks ago. The trial, which hopes to enroll 20 people, is mainly a safety assessment, but participants will go off ARVs, and then the researchers will closely monitor them to see whether their HIV levels rise or remain suppressed. “We’re going to find out very soon whether this is all a bunch of nonsense or actually works,” Fauci says.

Source: Science Mag

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