The researchers believe Keytruda and possibly other anti-PD-1 checkpoint inhibitors might help the immune system track the last signs of HIV while also preventing HIV’s ability to hide.
Merck’s Keytruda (pembrolizumab) is the company’s blockbuster checkpoint inhibitor used to treat numerous cancers. And now, a study published in Science Translational Medicine suggests it might help treat HIV.
Keytruda is an anti-PD-1 antibody. PD-1 stands for programmed cell death protein and is a protein found expressed by T cells during activation. It has a role in regulating the immune system’s response. Cancer cells often trigger PD-1 in order to hide from the immune system. Drugs like Keytruda block that interaction, allowing the immune system to work better against tumors.
HIV attacks and “lives” in CD4+ T cells, which express PD-1. The research evaluated the effect of Keytruda on the HIV reservoir — HIV levels in the T cells — in 32 people living with HIV who were on suppressive antiretroviral therapy and also diagnosed with cancer. The authors wrote, “They observed evidence of increased unspliced HIV RNA and the unspliced RNA: DNA ratio, consistent with anti-PD-1 treatment having the potential to reverse HIV latency.”
In a statement, Adeeba Kamarulzaman, President of the International AIDS Society, said, “This is an exciting advance. Being able to stop HIV from hiding is an important part of finding an HIV cure.”
Antiretroviral drugs are pretty good at suppressing HIV. Without those drugs, HIV proliferates, overwhelming the immune system. But the virus still hides out in reservoirs in the body, staying latent.
“But treatment can’t clear latent virus,” said Sharon Lewin, an HIV researcher at the University of Melbourne and senior author of the study. “And you always end up with exhausted T cells.”
Exhausted T cells generate PD-1. But PD-1 also can cause HIV to become senescent. Lewin said, “PD-1 causes a bit of trouble in HIV. It means you have an exhausted immune system that can’t clear [infected] cells, but you basically also silence the virus and put it in a latent form. So, you find a lot of these latent viruses inside cells that express PD-1.”
The researchers believe Keytruda and possibly other anti-PD-1 checkpoint inhibitors might help the immune system track the last signs of HIV while also preventing HIV’s ability to hide. “It has the potential to be a double whammy,” Levin said.
It’s not quite as easy as it sounds, however. Checkpoint inhibitors have potential side effects, including cytokine storms and neuroinflammation. Lewin notes that it’s challenging to use checkpoint inhibitors in people without cancer, and the studies that have been conducted were halted because of the side effects.
Lewin partnered with researchers at the Fred Hutchinson Cancer Research Center to find patients who were receiving Keytruda for cancer but were also receiving antiretroviral therapy for HIV. They received Keytruda, which is dosed via infusion, every three weeks for up to 105 weeks. They collected blood samples regularly and analyzed it for genetic signs of HIV.
Right after the first infusion, they found HIV genetic evidence in the blood, which suggested it was pushing the virus out of hiding and making it more vulnerable to the antiretroviral drugs as well as the body’s immune system. But it didn’t completely remove the HIV from the first five patient’s blood.
“It released the brakes on the virus, and now they’re visible to the immune system,” Lewin said. “But this is just a proof of concept. Anti-PD1 on its own repeatedly didn’t get rid of the reservoir.”
Much more research will be needed to see if this is practical.
Dr. Shyam Kottilil, an infectious disease doctor and Professor at the Institute of Human Virology at the University of Maryland School of Medicine, who was not involved in the research, told STAT, “It makes us more enthusiastic about cure efforts, but I would not say we are close.” He added the “major concern is safety of these agents in people with HIV without cancer.”
