Rutgers: HIV Hide and Seek

HIV persists in latently infected memory CD4+ T cells despite effective antiretroviral therapy, leading to rapid viral rebound upon cessation of treatment.  Latency-reversing agents (LRAs) are crucial for strategies to eliminate these reservoirs by reactivating the virus, making infected cells visible to the immune system.  Current LRAs often lack specificity, leading to off-target effects and potential toxicity.  The Gélinas Lab at Rutgers Center for Advanced Biotechnology & Medicine sought to develop a highly specific and potent LRA with fewer side effects.  They investigated GS143, a small molecule inhibitor of the E3 ubiquitin ligase β-TrCP, as a potential LRA for HIV-1.  

GS143

They demonstrated that GS143 effectively reactivates latent HIV-1 in both primary cell models and cells from antiretroviral therapy-treated individuals without inducing T cell activation, a significant advantage over many existing LRAs. They elucidated a novel mechanism of action for GS143, involving the unconventional activation of the NFκB pathway through NIK stabilization and IKK phosphorylation, leading to p65 phosphorylation and nuclear translocation.  Furthermore, they suggest a supporting role for β-catenin in this process.  GS143 represents a new class of LRAs with potential for development as part of a combination therapy to eradicate latent HIV-1 reservoirs.  Their research provides compelling evidence that GS143, a β-TrCP inhibitor, is a promising novel LRA for HIV-1. Its ability to potently reactivate latent virus without inducing T cell activation and its synergistic effects with other LRAs make it an attractive candidate for further drug development. The elucidation of its unconventional NFκB-dependent mechanism offers new insights into regulating HIV-1 latency and identifies a novel therapeutic target within the ubiquitin-proteasome system. They recommend further research to explore the in vivo efficacy and safety of GS143 and its potential role in combination strategies aimed at achieving HIV-1 remission or cure.

Sarkar S, Kobayashi Y, Russnak T, Shen J, Nahass RG, Dougherty JP, Gélinas C. GS143, an inhibitor of E3 ligase β-TrCP, reverses HIV-1 latency without activating T cells via unconventional activation of NFκB. PLoS Pathog. 2025 Apr 1;21(4):e1013018. doi: 10.1371/journal.ppat.1013018. PMID: 40168443; PMCID: PMC11999137. 

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013018#ppat.1013018.ref013