What if the presence of a well-known but misunderstood viral protein explains why some people living with HIV (PLWH) never recover their health, even with antiretroviral treatment?
Dr. Madeleine Durand and Andrés Finzi, researchers at the CRCHUM, Université de Montréal's affiliated hospital research centre, will explore this through the launch of a groundbreaking clinical trial this fall.
Two studies, one approach
With the publication of a remarkable study in 2023 , the two scientists and Mehdi Benlarbi, a PhD student in Finzi's lab, showed a keen interest in the HIV molecule gp120. The virus is known to infect CD4 cells responsible for activating the defences of the body's immune system, but the researchers suspected it does more than that.
In fact, in one in three people, gp120 circulates in the blood, acting as a viral toxin—even when the HIV viral load is undetectable. It attaches itself to healthy cells, targeting them for elimination by the immune system, which ends up destroying its own defences, as shown by Finzi's lab back in 2016.
In a new study , published in August 2025 in eBioMedicine, the CRCHUM scientific team shows that certain non-neutralizing antibodies, known as anti-cluster A antibodies, exacerbate this situation by attacking these uninfected CD4 cells made vulnerable by the action of gp120.
"This form of immune sabotage leads to a decrease in the number of CD4 cells and has a direct impact on the ability of the immune system of PLWH to fight the virus," explained Finzi, a professor of virology in UdeM's Faculty of Medicine.
"Conversely, in our study, we show that other rarer antibodies—anti-CD4 Binding Site (CD4BS) antibodies—block gp120 from binding to the surface of healthy CD4 cells and protect them," he added.
This discovery was made possible with blood samples from the Canadian HIV and Aging Cohort Study ( CHACS ) led by Dr. Madeleine Durand. This cohort included 850 PLWH and 250 control subjects.
"Only 15 percent of PLWH have these 'good' antibodies in their plasma, in addition to the 'bad' antibodies that get rid of healthy cells," said Durand, clinical professor at the Faculty of Medicine at Université de Montréal.
Fostemsavir: more than just an antiviral?
In a third study , published in The Journal of Infectious Diseases, the CRCHUM scientific trio, aided by Jonathan Richard, a research associate in Finzi's laboratory, shows that people treated with fostemsavir have lower levels of "bad" antibodies.
The research group had already demonstrated in a previous study that fostemsavir, a drug approved by Health Canada for PLWH in cases of treatment failure, blocked the toxic effect of gp120.
"This drug, produced and supplied by our partner ViiV Healthcare, deforms the viral protein in an unprecedented way," said Finzi. "There are less of the "bad" antibodies to label uninfected CD4 cells, as the drug renders gp120 incapable of sticking to these cells. It neutralizes its toxicity."
This mechanism, observed in samples from Italian and ViiV Healthcare biobanks, suggests that fostemsavir could improve immunity even in people with a well-controlled virus.
"It would restore CD4 cells to their role as the orchestra conductor of the immune system, and enable PLWH to enjoy better health," said Durand.
A two-year trial on 150 people
These scientific advances have led to the RESTART trial , a randomized controlled trial to be launched this fall at the CHUM, piloted by Durand. 150 people will be recruited and followed over a two-year period.
The goal is to test whether fostemsavir, combined with an existing antiretroviral therapy, can have beneficial effects on the cardiovascular health of people living with HIV.
In PLWH, the sustained activation of the immune system leads to chronic inflammation that can cause health problems such as cardiovascular diseases, osteoporosis or neurocognitive decline.
These problems, which clinicians call early-onset comorbidities, arise around 15 years earlier than in the general population.
"Our clinical trial is based on a personalized medicine approach", said Durand. Only PLWH with a detectable level of gp120 in their blood will be able to take part in the trial. A test developed by Finzi's team can detect this viral protein in the plasma of participants.
"Participants will undergo two cardiac CT scans, at the beginning and the end of the study, to measure coronary plaque progression," she said.
A marker of cardiovascular disease, this measurement is made through imaging and will be carried out by CRCHUM scientist Dr. Carl Chartrand-Lefebvre, director of UdeM's Department of Radiology, Radiation Oncology and Nuclear Medicine.
A different approach to treatment
Funded by the Canadian Institutes for Health Research, the RESTART trial offers a new way of thinking about HIV treatment. It is part of an effort to better understand the aging of people living with HIV and to improve their quality of life.
"Suppressing HIV viral load in plasma with antiretrovirals, the current standard of treatment, may not be enough," said Durand. "If our clinical trial confirms that soluble gp120 is a legitimate therapeutic target, we will then have several additional ways to attack the virus, whether with a drug or broadly neutralizing antibodies targeting the CD4BS."
According to the World Health Organization, almost 41 million people were living with HIV in 2024 and 1.3 million people acquired HIV.
Author: Bruno Geoffroy
