Researchers at the University of Montreal's CRCHUM are launching a groundbreaking clinical trial this fall to test whether targeting a toxic HIV protein could improve health outcomes for people living with HIV, even when their viral load is undetectable. The RESTART trial represents a paradigm shift from focusing solely on viral suppression to addressing the complex immunological aftermath of HIV infection.
The gp120 Discovery
The investigation centers on gp120, an HIV envelope glycoprotein that Dr. Madeleine Durand and Andrés Finzi discovered acts as a persistent toxin in the bloodstream. Their 2023 study revealed that in approximately one-third of people living with HIV (PLWH), gp120 remains detectable in plasma even when viral particles are effectively suppressed by antiretroviral therapy.
"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.
The toxic mechanism works by gp120 binding to healthy CD4+ T cells, flagging these crucial immune cells for destruction by the immune system itself—a process Finzi's laboratory first uncovered in 2016. This immune self-sabotage erodes the very defenses needed to control the virus, contributing to immune system deterioration despite effective therapy.
Antibody Dynamics Revealed
A new study published in August 2025 in eBioMedicine shed light on the antibody-mediated dynamics that exacerbate this phenomenon. The CRCHUM team identified anti-cluster A antibodies, a subset of non-neutralizing antibodies that attack uninfected CD4+ cells rendered vulnerable by gp120 interaction.
However, the researchers also discovered a protective counterforce: anti-CD4 binding site (CD4BS) antibodies that block gp120 from binding to healthy cells. "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.
These findings emerged from analysis of blood samples from the Canadian HIV and Aging Cohort Study (CHACS), which included 850 PLWH and 250 control subjects.
Fostemsavir's Unique Mechanism
The research team's attention turned to fostemsavir, a drug approved by Health Canada for PLWH in cases of treatment failure. Their study published in The Journal of Infectious Diseases demonstrated that people treated with fostemsavir have lower levels of harmful antibodies.
"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."
The mechanism observed in samples from Italian and ViiV Healthcare biobanks suggests that fostemsavir could improve immunity even in people with a well-controlled virus by restoring CD4 cells to their role as the orchestra conductor of the immune system.
The RESTART Trial Design
Building on these scientific advances, the RESTART trial will recruit 150 participants over a two-year period to test whether fostemsavir, combined with existing antiretroviral therapy, can benefit cardiovascular health in people living with HIV.
The study employs a personalized medicine approach, enrolling only PLWH with detectable gp120 levels in their blood, identified through a test developed by Finzi's team. "Our clinical trial is based on a personalized medicine approach," said Durand.
Participants will undergo cardiac CT scans at the beginning and end of the study to measure coronary plaque progression, a validated marker of cardiovascular disease. These assessments will be conducted by CRCHUM scientist Dr. Carl Chartrand-Lefebvre, director of UdeM's Department of Radiology, Radiation Oncology and Nuclear Medicine.
Addressing Early-Onset Comorbidities
The trial addresses a critical unmet need in HIV care. In PLWH, sustained immune system activation leads to chronic inflammation causing health problems such as cardiovascular diseases, osteoporosis, and neurocognitive decline. These early-onset comorbidities arise around 15 years earlier than in the general population.
"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."
Global Impact Potential
The research comes at a critical time, with the World Health Organization reporting that almost 41 million people were living with HIV in 2024 and 1.3 million people acquired HIV. The RESTART trial, funded by the Canadian Institutes for Health Research, offers a new way of thinking about HIV treatment as part of efforts to better understand aging in people living with HIV and improve their quality of life.
This cutting-edge research not only deepens understanding of HIV pathogenesis but also paves the way for innovative clinical interventions tailored to the complex immunological landscape of people living with HIV, potentially moving the field closer to fully restoring health and immune competence in this vulnerable population.
