A combination of four drugs can flush out HIV-infected cells from hidden reservoirs in the body and kill them with a boost to the immune system, according to research published in the journal Cell today. The finding takes scientists one step closer to a HIV cure.
Although the research was done in mice, head of the infectious diseases unit at The Alfred Hospital, Professor Sharon Lewin said it was a significant step in HIV cure research.
When a person is infected with HIV, some of the virus can go into hiding by burrowing into the DNA where the immune system can’t see it. This is called HIV latency. In patients on anti-HIV drugs, latent virus can persist indefinitely.
The “shock-and-kill” approach used in the research induced these hidden or latent viruses to resurface by using a combination of three drugs.
“It proves the principle that a combination of drugs that activate latent virus together with antibodies can induce remission – at least in a slightly artificial HIV-infected mouse model,” she said.
Professor Lewin said the principle wasn’t new.
“This has been an idea we have been exploring for many years in test tube models of HIV latency and more recently in clinical trials. In the few clinical trials recently completed, a range of drugs that are used for treating cancer could wake up latent virus in people but the infected cell wasn’t killed,” she said.
To kill the cells, the researchers boosted the mice’s immune systems using powerful antibodies known as “broadly neutralising antibodies”.
More than half (57%) of the HIV-infected mice treated with the combination activating drugs together with these antibodies could keep the virus under control.
Scientia Professor of Medicine David Cooper, director of the Kirby Institute at UNSW said the research represented an important model but added it was difficult to extrapolate the results to humans.
“The mice were treated with the antiretroviral therapies within a day or two of infection and that is not the case globally. People don’t usually know they’re infected as soon as that,“ he said.
“Many people in low- and middle-income countries aren’t identified until they get an opportunistic infection like tuberculosis and at that late stage, the amount of latent virus is very large,” he added.
One unique aspect of the research was the use of three drugs to induce the latent infected cells to come out of hiding.
Professor Lewin said there had been clinical trials using one drug to activate the latent virus and it was known that using two drugs to activate latent virus – at least in test tube models – led to a better effect than each alone, but a combination of drugs have not yet been tested in clinical trials.
“This study went a step further and used three, showing that three drugs are better than two, which is better than one,” she said. “And these drugs worked in keeping the virus under control when combined with one of these potent antibodies.”
Professor Cooper raised concerns about the toxicity of the drug combination used in the research.
“One of the agents that they used in the study has been approved to treat a rare type of lymphoma, and it’s fair to say that it’s not a particularly light therapy,” he said. “It’s possible that the other types of drugs they use to shock might have these sort of toxicities. It’s very hard to tell in these mice, what the toxicities of these drugs are.”
Both Lewin and Cooper agreed that safety was a key concern when trying to activate latent virus, given antiretroviral therapies were safe and allowed people with HIV to have a normal lifespan.
“What is interesting here is the role of broadly neutralising antibodies in eliminating latent virus,” Professor Lewin said. “These antibodies have recently been shown in monkeys to work well in preventing infection. And there are studies giving broadly neutralising antibodies to monkeys and humans on antiretroviral treatment to see if they can help keep the virus in remission.”
“Whether you need three agents to activate latent HIV and whether that’s even feasible given potential drug interactions, I’m not sure. But it is exciting because it shows broadly neutralising antibodies and combination activation could play a role in the kick-and-kill strategy,” she said. “That has not been shown before.”