Monkeys May Lead the Way for Immunotherapy HIV Cure

Heather Boerner

July 21, 2021

A small study conducted in rhesus macaques found a 10-fold reduction in HIV viral load when the monkeys received immunotherapy to block programmed cell death protein–1 (PD-1) and the cytokine interleukin-10 (IL-10). Additionally, 8 of 10 monkeys in the study experienced HIV-like simian immunodeficiency virus (SIV) levels of <1000 copies for up to 12 weeks. Results from the study were presented at the International AIDS Society (IAS) Conference 2021, held virtually.

This doesn't mean that IL-10 and PD-1 immunotherapy will cure HIV in humans, said Tim Schacker, MD, vice dean for research and the University of Minnesota Medical School, Minneapolis, Minnesota. But it does open another door on the way to functional cure. The study will need to be replicated by other labs and in humans, and it's likely, he said, that this approach would need to be combined with others to really control HIV.

"Every single one of my patients from age 16 to 80 want to be cured, and they want to know when it's going to happen," Schacker told Medscape Medical News. "This data gets us a little closer to saying that there are some interventions we can make to alter the curve a little bit. What can we do to alter the curve more, and at what point do we get to the point that we've got a functional cure? We're not there yet."

In this trial, Zachary Strongin, an immunology and molecular pathogensis graduate student at Emory University, Atlanta, Georgia, and team targeted IL-10 and PD-1 as important pathways by which HIV escapes detection by the immune system.

"PD-1 and IL-10 both operate to prevent effective clearance of viral infections, but do so through unique mechanisms," Strongin said. "Blocking only one of the signaling pathways may lead to compensation for the other suppressive pathways. So a combination IL-10 and PD-1 blockade represents a promising approach to target persistent viral suppression," he said.

Mindful of the pitfalls of previous monkey studies of HIV, the Emory team designed the trial to make it difficult for the drug combination to yield better results than might be realistic in humans. For example, this trial exposed 28 rhesus macaques to SIVmac239, a highly pathogenic strain of SIV. Previous studies have used weakened versions of SIV; those trials caused early excitement, but the results couldn't be replicated in humans.

In the current study, the animals were left without treatment for 42 days in order to mimic the experiences of people with HIV who don't find out they are living with HIV until they've had it for a while. Many trials test potential cures in monkeys or humans who were in the early days of infection in an effort to prevent the virus from establishing deep reservoirs of HIV that lie dormant before emerging and replicating again. These reservoirs are one of the reasons HIV treatments stop working as soon as patients stop taking the medicines.

The approach used by the investigators allowed the establishment of viral setpoints — that is, a stable level of virus after the peak of acute infection. These setpoints might make it harder to cure HIV.

The monkeys were then given antiretroviral treatment (ART) for 14 months. Three months before ART was stopped, the researchers divided the monkeys into three groups. One group, comprising eight monkeys, received a placebo. The second group, with 10 monkeys, received infusions of 10 mg/kg of the anti-IL-10 drug every 3 weeks. The third group, with 10 monkeys, received both the IL-10 agonist and 10 mg/kg of an anti-PD-1 antibody every 3 months. The monkeys continued to receive these doses for 14 weeks after ART was discontinued.

The researchers took blood and tissue samples to see whether PD-1 and IL-10 were indeed turned off. They tracked HIV viral load and CD4 T-cell counts to see whether and when HIV rebounded. Such rebounds would indicate that the treatment had stopped working in the absence of ART.

When the researchers discontinued ART, the virus spiked in the monkeys but then settled to a setpoint. That setpoint was 10-fold lower in the monkeys that received IL-10 monotherapy and dual IL-10 therapy than in the monkeys in the control group. What's more, the viral loads after immunotherapy were also 10-fold lower than they were after initial infection, indicating that the treatment might have altered stubborn HIV reservoirs. After the final dose of IL-10 and PD-1 antibodies, the monkeys that received both treatments experienced a 40-fold drop in viral load from the levels before ART was initiated.

In addition, for 8 of the 10 monkeys that received the combination of IL-10 and PD-1 drugs, viral loads were <100 copies/mL at least once after treatment was interrupted; this occurred in only one monkey in the control group. Strongin characterized the results as indicating "robust, sustained control of viremia through the [analytic treatment interruption] period."

"This is a remarkably low level of viral load for the pathogenic SIVmac239," he said.

Indeed, part of the excitement about the study for Steven Deeks, MD, professor of medicine in residence at the University of California, San Francisco, was the robust response in the face of several challenges, he said in an interview with Medscape.

"People in our field find this very exciting, that they were able to actually move the dial, so to speak, on such a tough model," said Deeks, who was not involved in the trial.

Schacker, who is pursuing another immunotherapy approach to HIV cure, also sees this advance as a great opportunity to offer a wider range of treatments to fully control HIV.

"It's going to take multiple interventions working at different parts [of the HIV life cycle]. That's the big take-home message here," he said. "The field is inching towards being able now to put some interventions together to see if there's a synergy or not. This data would suggest that there are at least two interventions."

The study was funded by Merck, the National Institutes of Health National Institute of Allergy and Infectious Diseases, and Emory University. Strongin, Deeks, and Schacker report no relevant financial relationships.

International AIDS Society (IAS) Conference 2021: Abstract 2485. Presented July 20, 2021.

Heather Boerner is a science and medical reporter based in Pittsburgh, PA and can be found on Twitter at @HeatherBoerner. Her book, Positively Negative: Love, Sex, and Science's Surprising Victory Over HIV, came out in 2014.

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