Dendritic Cells Potently Purge Latent HIV-1 in TCR-Activated Cells via the PI3K-Akt-mTOR Pathway: Implications for ‘Shock and Kill’ Strategies and Reservoir Analysis
The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we demonstrate that TCR-stimulated effector T cells still frequently harbor latent HIV-1. Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with dendritic cells (DCs) triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4+ T cells from aviremic patients receiving TCR+DC-stimulation reversed latency more frequently. Such a “one-two punch” strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4+ T cells. This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.
van Montfort, Thijs and van der Sluis, Renée and Darcis, Gilles and Beaty, Doyle and Groen, Kevin and Pasternak, Alexander O. and Pollakis, Georgios and Vink, Moniek and Westerhout, Ellen M. and Hamdi, Mohamed and Bakker, Margreet and van der Putten, Boas and Jurriaans, Suzanne and Prins, Jan and Jeeninga, Rienk and Thomas, Adri A.M. and Speijer, Dave and Berkhout, Ben, Dendritic Cells Potently Purge Latent HIV-1 in TCR-Activated Cells via the PI3K-Akt-mTOR Pathway: Implications for ‘Shock and Kill’ Strategies and Reservoir Analysis (2018). Available at SSRN: https://ssrn.com/abstract=3192030 or http://dx.doi.org/10.2139/ssrn.3192030
This version of the paper has not been formally peer reviewed.
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