Targeting Soluble gp120 to Combat Immune Dysfunction in People Living with HIV

At CROI 2025, we spoke with three researchers from Université de Montréal about the role of soluble gp120 (sgp120) in people living with HIV (PLWH). Mehdi Benlarbi, a PhD student explained how sgp120 may contribute to immune dysfunction, even in individuals with undetectable viral loads on ART.

“We believe that soluble gp120, as a viral fragment, can persist in the body even if viral replication is under control with ART,” said Benlarbi. “This persistence leads to chronic inflammation, which may be a factor in the inability of some PLWH to recover their CD4+ T cell counts, despite undetectable viral loads.”

This observation is key to understanding the ongoing challenges faced by PLWH, particularly as they age. “A low CD4 count increases the risk of comorbidities such as cardiovascular disease and cancers,” Benlarbi added. “If we can target sgp120, we may be able to improve immune recovery and reduce the associated risks.”

This research has led to the development of the RESTART study, a clinical trial that is grounded in the work of Mehdi Benlarbi and Professor Andrés Finzi, PhD on sgp120 and fostemsavir. The study aims to explore whether fostemsavir, an investigational therapy, can reduce immune dysfunction and inflammation in PLWH by targeting sgp120. Additionally, it will investigate whether this approach could improve cardiovascular outcomes, given the role of inflammation in the development of cardiovascular disease in PLWH.

Soluble gp120 remains detectable even after ART initiation, suggesting that it may contribute to ongoing immune dysfunction in PLWH. ART suppresses HIV replication effectively, yet many individuals experience immune system impairments, particularly in CD4+ T cell recovery. Preliminary data show a negative correlation between sgp120 levels and CD4+ T cell counts, indicating that sgp120 may impede immune recovery despite viral suppression.

Finzi elaborated on this mechanism, “We view soluble gp120 as a toxin that can engage the CD4 receptor,” said Finzi. “If we could block the ability of gp120 to engage the CD4 receptor, we could neutralize its toxic effect. Fostemsavir, a small molecule inhibitor, can prevent gp120 from binding to CD4, which may alleviate the immune dysfunction caused by this viral protein.”

Fostemsavir has demonstrated in vitro the ability to prevent the interaction between gp120 and CD4, protecting uninfected cells from immune system targeting. This suggests that fostemsavir may help reduce chronic inflammation in PLWH, even with undetectable viral loads.

The RESTART study is a randomized, community-driven clinical trial designed to evaluate fostemsavir’s effects as an add-on therapy to standard ART. Co-designed with a community advisory group of people living with HIV, the study will recruit 150 participants who are 40 years or older, or who have lived with HIV for 25 years or more. All participants will be on ART with undetectable viral loads but detectable sgp120 levels in plasma.

Participants will be randomly allocated to either receive fostemsavir as an add-on to their standard ART regimen or remain on their standard care for two years. The primary goals of the study are to assess the impact of fostemsavir on immune function, inflammation, and cardiovascular health in PLWH.

Madeleine Durand, MD, MSc, associate professor of medicine and a researcher at the CHUM Research Centre, explained the study’s scope, “The research by Andrés and Mehdi gives us hope that targeting residual viral proteins, such as sgp120, could reduce inflammation and immune dysfunction in people living with HIV,” Durand said. “In the RESTART study, we will evaluate whether adding fostemsavir to standard ART can improve immune recovery and reduce the risk of cardiovascular disease.”

Participants will undergo baseline and end-of-study cardiac CT scans to assess whether fostemsavir treatment is associated with a reduction in coronary atherosclerosis, a key indicator of cardiovascular disease. This will provide valuable insights into whether targeting sgp120-associated inflammation can have a beneficial effect on cardiovascular health in PLWH.

Reference

Benlarbi M, Finzi A, Durand M, et al. Impact of ART Initiation on HIV-1 Soluble gp120 Levels and CD4 Counts in PWH. Poster #352 presented at CROI 2025. March 9-12, 2025, San Francisco, California.