The human immune system, when fighting HIV, sometimes resembles a panicked security guard shooting at both intruders and innocent bystanders. Now researchers at the University of Montreal Hospital Research Centre have found that an existing HIV medication might stop that friendly fire.
In a series of studies published this fall, scientists discovered that fostemsavir, a drug already approved for people with treatment-resistant HIV, appears to reduce harmful antibodies that attack the body’s own healthy immune cells. The finding suggests the medication could offer benefits beyond its original purpose of blocking viral entry into cells.
When the Body Attacks Itself
The problem centers on gp120, a viral protein that does more damage than previously understood. In about one-third of people living with HIV, this molecule circulates in the bloodstream even when the virus itself is undetectable. Once released, gp120 latches onto healthy CD4 cells, which coordinate immune responses. The immune system then mistakes these healthy cells for infected ones and destroys them.
“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 Andres Finzi, a professor of virology at the University of Montreal’s Faculty of Medicine.
The research team analyzed blood samples from 850 people living with HIV and 250 control subjects through the Canadian HIV and Aging Cohort Study. They found that certain antibodies, called anti-cluster A antibodies, worsen this self-destruction by targeting healthy CD4 cells marked by gp120. Only 15 percent of people with HIV produce protective antibodies that block this process.
An Unexpected Side Effect
Fostemsavir was designed to prevent HIV from entering cells by binding to gp120 and deforming it. But the researchers noticed something unexpected in patients taking the drug: their levels of harmful antibodies dropped significantly.
The team examined blood samples from participants in two clinical trials and one real-world registry. In both groups receiving fostemsavir, levels of anti-gp120 antibodies declined markedly over 8 to 12 weeks. A control group taking different HIV medications showed no such decrease, despite similarly reduced viral loads.
“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,” said Finzi.
Laboratory tests confirmed that plasma from treated patients showed reduced ability to recognize and attack healthy CD4 cells coated with gp120. The decline in harmful antibodies correlated with improvements in CD4 counts, the key measure of immune system health in people with HIV.
Dr. Madeleine Durand, who led the clinical research, noted that people living with HIV experience cardiovascular disease, osteoporosis, and cognitive decline about 15 years earlier than the general population. These early-onset health problems stem from chronic inflammation driven by persistent immune system activation.
This fall, Durand will launch the RESTART trial at the University of Montreal Hospital Centre. The two-year study will enroll 150 participants with detectable gp120 levels to test whether adding fostemsavir to standard antiretroviral therapy improves cardiovascular health. Participants will undergo cardiac CT scans at the beginning and end to measure coronary plaque progression.
The trial represents a shift in thinking about HIV treatment. Current therapy focuses on suppressing viral replication, measured by viral load in the blood. But that metric may not capture the full picture of what the virus does to the body.
If the trial confirms that gp120 is a worthwhile therapeutic target, doctors could have new options for attacking HIV beyond traditional antiretrovirals. The approach might involve medications like fostemsavir or specialized antibodies targeting specific parts of the viral protein.
The World Health Organization estimates that nearly 41 million people were living with HIV in 2024. Most take antiretroviral medications that successfully suppress the virus to undetectable levels, but many still experience accelerated aging and health complications. Understanding why some people never fully recover their health, despite treatment, remains one of the persistent puzzles in HIV care.
The research team’s work suggests that viral proteins circulating in the bloodstream, invisible to standard viral load tests, may be partly responsible. Whether targeting these proteins can close the 15-year gap in healthy life expectancy between people with and without HIV will require years of additional study.
Journal of Infectious Diseases: 10.1093/infdis/jiaf461
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