A 3D illustration of the human immunodeficiency virus. Image credit: Shutterstock
More than 50 years after it jumped the species barrier and became one of the most devastating viruses to affect mankind, HIV remains a stubborn adversary.
Treatment has improved dramatically over the past 20 years, but people who are infected will remain so for the rest of their lives, and must take one pill daily – at one time it was a cocktail of 30.
But now, as another World Aids Day pulls into view, scientists are beginning to ask if the biggest breakthrough – an out-and-out cure for the tens of millions who have contracted the virus – could be in sight.
The excitement lies in research that is having some success in drawing the virus out of a latent stage (in which it can lie undetected for long periods) so that it could be destroyed.
“The last couple of years have been very exciting on this front,” said Satish Pillai, an associate professor in HIV research from the University of California San Francisco.
“We’re now attempting find the holy grail of HIV research.”
“In the first instance, we want to identify the signature characteristics, in a reliable and accurate way, of latently infected cells,” Pillai said, speaking of HIV-infected cells that evade current treatments. “The other side is that we’re developing novel strategies to destroy them once we’re able to identify them.”
“We’re entering this new era of finding a functional cure to eradicate the virus,’ he explains.
The difficulty in dealing once and for all with HIV is that, unlike other viruses, HIV-infected cells are able to “hide” by entering a resting phase that makes them invisible to our immune system and current treatment therapies.
These ‘latently infected’ cells then exist in reservoirs in the bodies of those with the virus, and can launch new, resistant attacks if treatment is discontinued.
Over the last few years, scientists have determined that destroying this last reservoir of cells will be the future of a cure.
“People have been looking into latency long before this became a focus for a cure,” said Dr Jonathan Angel, chief of the Division of Infectious Diseases at Ottawa Hospital Research Institute.
“There have been people working on HIV research for a long time, but only recently has the tone shifted.’
“In my personal opinion, our therapies have become so good that looking at better therapies has become futile. People are taking a pill once a day with no side affects. That’s hard to improve upon.”
In fact, the increased efficacy of antiretrovirals has curbed the deadliness of the disease significantly. The virus exists in around 36.7 million people around the world and, although it killed around 1 million people in 2017 according to UNAids, that represents a drop of almost 50% from 2005, when mortality from Aids-related illnesses was at its peak.
This drop is due to improved medicine, as well as logistics and patient awareness. But the virus remains a grave health problem in rural areas that lack these resources, especially in regions such as Africa – more than a quarter of people in Swaziland have the virus.
The deadliness of the disease in some regions, the tremendous expense and the pressure on patients, means that a cure remains an important goal. There are a number of different approaches currently being studied.
One approach, often named the “kick and kill” or “shock and kill”, aims to kick the resting cells out of their sleep so they can be pinpointed and eliminated.
Sarah Fidler, professor of HIV medicine at Imperial College London, who recently led a major study testing the efficacy of the kick and kill method said: “The idea is to reactivate the latent cells so they start producing the proteins on their surface so they look different from healthy cells. We would do this with some kind of drug, which is what we’re in the process of determining.”
The other research approach wants to find and destroy the HIV-infected cells while they’re still in the resting state.
The key to doing this would be finding something distinct about an infected, resting cell – as opposed to a healthy one – so that an antiviral agent can target them. Scientists call this elusive target a biomarker.
There is promising work being done with antiviral-viruses – viruses that are engineered to target and destroy other viruses. A specific strain, the rhabdovirus called Maraba virus (MG1), has been engineered to seek out faulty cell communication, something that happens in both cancer and HIV. A difference as small as this, between healthy and unhealthy cells, is enough for something like MG1 to target.
Angel says the MG1 approach only occurred because of the physical proximity of scientists researching cancer and HIV.
“The MG1 project came up on the side from being on the same floor as oncology, and seeing seminars from guys in cancer research,” Angel said. “There are viruses that are able to kill cancer cells based on the fact that they have impaired interferon signalling [proteins made by cells to prevent virus replication]. This is an innate antiviral molecule, present in all of our cells to ward off viruses.
“We know that HIV can interfere with those pathways, but what is not known is whether that is the case with latently infected cells, because they occur with such a low frequency in the body.
“MG1 as a potential therapeutic agent that can exploit these cells.”
Although there is consensus that destroying the virus reservoirs is the next step, there are disagreements about whether this could be properly called a cure, as we understand the term.
“Completely eliminating the reservoirs of HIV would result in a cure. The dissension might exist on what is referred to as a ‘functional cure’,” Angel said.
“This refers to establishing a state where the immune system itself (without antiretroviral therapy) can control the virus so it is not detectable in the blood and there is no effect on the immune system.
“While the scientific community might consider this a cure, the general public might not,” he said.
The speed of the research has been made possible because of the advocacy community that stands behind it, says Fidler. “We are talking about a community of people with HIV that have been an extraordinary driver in researching the condition,’she said. “In our most recent trial, no-one dropped out, which is practically unheard of.”
“It’s still a very stigmatising condition. People don’t feel comfortable with talking about it, as they might with diabetes or cancer,” Fidler said.
“I think it motivates this collaboration. People still feel that they are somehow different and that’s what makes people join together, they relate to these other people who have the virus. They are a potent advocacy force.”