Work

CD32 does not mark the HIV-1/SIV latent reservoir

Year: 2017

Type: article

Abstract: mainly comprised of resting CD4 T cells.Cells harboring latent provirus typically display little to no HIV-1 gene expression and thus remain invisible to the immune system.To achieve a sustained viral remission in HIV-infected patients off ART, it will be important to both reduce the size of the reservoir and to control viral rebound by eliciting an effective immune response capable of restraining viral spread from the smaller reservoir.One approach involves the combined use of potent and safe latency-reversing agents (LRAs) and a therapeutic vaccine.Our recent studies have shown that activators of the AKT/mTOR pathway form a promising group of LRAs.Our interest has focused on two small molecules, SB-216763 and Tideglusib that commonly inhibit glycogen synthase kinase-3 (GSK-3).This inhibition results in sequential activation of mTORC2, AKT, and mTORC1.Both compounds are known to have high tissue penetration, including entry into the brain.Methods: Following treatment of CD4 T cells with the LRAs, we quantified virus production with digital droplet PCR.We assessed viability and T cell activation with flow cytometry, and we characterized the molecular mechanism of these two inhibitors using a combination of immunoblotting, phosphoproteomics and RNA sequencing.Results: We found that SB-216763 and Tideglusib potently activate latent HIV-1 in both a tissue-based model of latency, and in CD4 T cells isolated from HIV-infected donors on ART.In some experiments these agents are more potent than anti-CD3/anti-CD28 antibodies and latency reversal is not associated with T cell activation as measured by changes in CD69 and CD25 expression.Finally, in contrast to the undesirable compromise of CTL/NK function associated with many first generation LRAs, GSK-3 inhibitors have been reported to enhance CTL and NK cell effector function.Conclusions: In summary, our findings reveal GSK-3 inhibitors as a new class of potent, safe, non-cell activating LRAs.Next, it will be key to define their activity in vivo using SIV-infected macaques.The fact that Tideglusib is already in phase IIb human trials for myotonic dystrophy and autism could accelerate its testing in HIV-infected patients.

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)30524-0