Antiretroviral therapy, the standard treatment for HIV, can remove any trace of the virus from the blood, but a hidden reservoir of HIV persists in patients who are in treatment. That means patients are never truly cured and need to be on HIV drugs for the rest of their lives.
Researchers have yet to discover a way to eliminate the virus in its latent stage, but new, early-stage research suggests a landmark cancer drug — pembrolizumab, also known as Keytruda — may be able to help. In a study published Wednesday in Science Translational Medicine, researchers looked at 32 patients that had both cancer and HIV and found that pembrolizumab, which revives the immune system and encourages it to attack tumors, also has the ability to flush HIV out of its hiding spot in immune cells.
“This is an exciting advance,” Adeeba Kamarulzaman, the president of the International AIDS Society, said in a statement. She was not involved in the study. “Being able to stop HIV from hiding is an important part of finding an HIV cure.”
HIV attacks the immune system by infecting white blood cells known as T cells. Without antiretroviral drugs, the virus will proliferate wildly through the body, obliterating the immune system and eventually leading to the patient’s death. There are effective treatments for HIV that can stop the virus from replicating and give the immune system a chance to recover.
“But treatment can’t clear latent virus,” explained Sharon Lewin, an HIV researcher at the University of Melbourne and the senior author on the study. “And you always end up with exhausted T cells.”
These cells weaken the immune system and make it harder for it to fight diseases. Exhausted T cells often make a molecule called PD1, which stands for programmed death 1, a compound that suppresses the immune system and puts immune cells in a state of stupor. At the same time, PD1 can cause HIV to go quiet as well.
“PD1 causes a bit of trouble in HIV,” Lewin said. “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 PD1.”
That’s where the pembrolizumab comes in. The drug, first approved by the FDA in 2014 for use against advanced melanoma, binds to PD1 and takes it out of play. In cancer, this revs the immune system up to destroy tumor cells. It’s also made the drug a blockbuster and one of the most effective treatments for a range of cancers. In HIV, it may also help the immune system hunt down the last vestiges of HIV while also disrupting the virus’ ability to hide. “It has the potential to be a double whammy,” Lewin said.
But testing the drug’s potential in HIV treatment poses challenges, because pembrolizumab and similar cancer immunotherapy drugs can have severe toxic side effects. Boosting the immune system with them is a double-edged sword. They can lead immune cells to kill tumors, but they can also cause the immune system to become overactive and lash out against the body’s healthy tissues, too.
“It’s challenging to give anti-PD1 drugs to people who don’t have cancer. There have been small studies, but they were stopped because of the side effects,” Lewin said.
So Lewin and her collaborators at the Fred Hutchinson Cancer Research Center had to find people who were both on antiretroviral therapy for HIV and were already being treated with pembrolizumab for cancer. They found 32 individuals who fit the bill and tracked levels of HIV in their blood throughout the course of their treatment.
Patients received an infusion of pembrolizumab every three weeks for up to 105 weeks, depending on how they responded to the drug. During that time, researchers regularly collected blood and analyzed it for HIV genetic material.
After the first infusion of pembrolizumab, the team began finding HIV genetic material in the patients’ blood, suggesting the drug was forcing the virus out its sanctuary and making it again vulnerable to the antiretroviral treatment and the body’s natural defenses. But, Lewin added, it wasn’t enough to free the patient of HIV entirely.
“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.”
Still, it’s an important step toward finding a cure to HIV, said Steven Deeks, a professor of medicine at the University of California, San Francisco, and an HIV expert who worked on the study with Lewin. For decades, scientists looked for a powerful weapon against the latent reservoir of HIV that can finish the infection off once and for all.
“But we now have this road map saying, ‘OK, let’s try low doses. Let’s try other ways to manipulate the system in the same pathway,’” Deeks said. “And that’s why this is an important advance.”
Experts said far more research is needed to figure out where the road map leads.
“It makes us more enthusiastic about cure efforts, but I would not say we are close,” said Shyam Kottilil, an infectious disease physician and professor at the Institute of Human Virology at the University of Maryland School of Medicine. Kottilil, who was not involved in the research, added that ” major concern is safety of these agents in people with HIV without cancer.”
Because drugs like pembrolizumab can have such severe toxicity, scientists must see if there’s a dose that can effectively do the job without causing severe side effects or death. And more broadly, scientists must still understand whether and how drugs like pembrolizumab might play a role in treating HIV, and find the best way to use these drugs to fully clear the virus from the body.
That work has already started, Lewin said, including a planned study to give a low level of pembrolizumab to patients living with HIV who don’t also have cancer. It’s possible that study might yield better results, too, she said, since the cancer may have interfered with the body’s ability to take full advantage of the drug’s effect on HIV.
“There’s a lot of avenues being tested now,” she said.
Helen Branswell contributed reporting.