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
PY - 2019/4/1
Y1 - 2019/4/1
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85062031306&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30824386
U2 - 10.1016/j.ebiom.2019.02.014
DO - 10.1016/j.ebiom.2019.02.014
M3 - Article
C2 - 30824386
VL - 42
SP - 97
EP - 108
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
ER -