Renée Marije van der Sluis

TY - JOUR

T1 - Dendritic cells potently purge latent HIV-1 beyond TCR-stimulation, activating the PI3K-Akt-mTOR pathway

AU - van Montfort, Thijs

AU - van der Sluis, Renée

AU - Darcis, Gilles

AU - Beaty, Doyle

AU - Groen, Kevin

AU - Pasternak, Alexander O

AU - Pollakis, Georgios

AU - Vink, Monique

AU - Westerhout, Ellen M

AU - Hamdi, Mohamed

AU - Bakker, Margreet

AU - van der Putten, Boas

AU - Jurriaans, Suzanne

AU - Prins, Jan H

AU - Jeeninga, Rienk

AU - Thomas, Adri A M

AU - Speijer, Dave

AU - Berkhout, Ben

N1 - Copyright © 2019. Published by Elsevier B.V.

PY - 2019/4/26

Y1 - 2019/4/26

N2 - 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.

AB - 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.

KW - Activated T cells

KW - Akt

KW - Dendritic cells

KW - Latency

KW - PI3K

KW - mTOR

U2 - 10.1016/j.ebiom.2019.02.014

DO - 10.1016/j.ebiom.2019.02.014

M3 - Journal article

C2 - 30824386

VL - 42

SP - 97

EP - 108

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -