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

Autor:	van Montfort T; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands. Electronic address: T.vanmontfort@amc.uva.nl., van der Sluis R; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Darcis G; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands; Department of Infectious Diseases, Liege University Hospital, Liege, Belgium., Beaty D; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Groen K; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Pasternak AO; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Pollakis G; Department of Clinical Infection, Microbiology and Immunology (CIMI), University of Liverpool, Liverpool, 8 West Derby Street, United Kingdom., Vink M; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Westerhout EM; Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Hamdi M; Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Bakker M; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., van der Putten B; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Jurriaans S; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Prins JH; Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Jeeninga R; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Thomas AAM; Department Developmental Biology, Faculty Beta-Science, Utrecht, Padualaan 8, 3584, CH, the Netherlands., Speijer D; Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands., Berkhout B; Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2019 Apr; Vol. 42, pp. 97-108. Date of Electronic Publication: 2019 Feb 26.
DOI:	10.1016/j.ebiom.2019.02.014
Abstrakt:	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. (Copyright © 2019. Published by Elsevier B.V.)
Databáze:	MEDLINE
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