Dendritic cells potently purge latent HIV-1 beyond TCR-stimulation, activating the PI3K-Akt-mTOR pathway

Thijs van Montfort, Renée van der Sluis, Gilles Darcis, Doyle Beaty, Kevin Groen, Alexander O. Pasternak, Georgios Pollakis, Monique Vink, Ellen M. Westerhout, Mohamed Hamdi, Margreet Bakker, Boas van der Putten, Suzanne Jurriaans, Jan H. Prins, Rienk Jeeninga, Adri A. M. Thomas, Dave Speijer, Ben Berkhout

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: 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 supply evidence that TCR-stimulated effector T cells still frequently harbor latent HIV-1. Methods: Primary HIV-1 infected cells were used in a latency assay with or without dendritic cells (DCs)and reversion of HIV-1 latency was determined, in the presence or absence of specific pathway inhibitors. Findings: Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs)did not overcome latency. However, interaction of infected effector cells with 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. Interpretation: This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.
Original languageEnglish
Pages (from-to)97-108
JournalEBioMedicine
Volume42
DOIs
Publication statusPublished - 1 Apr 2019
Externally publishedYes

Cite this

van Montfort, T., van der Sluis, R., Darcis, G., Beaty, D., Groen, K., Pasternak, A. O., ... Berkhout, B. (2019). Dendritic cells potently purge latent HIV-1 beyond TCR-stimulation, activating the PI3K-Akt-mTOR pathway. EBioMedicine, 42, 97-108. https://doi.org/10.1016/j.ebiom.2019.02.014