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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

DOI

  • Thijs van Montfort, 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.
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  • Renée van der Sluis
  • Gilles Darcis, 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.
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  • Doyle Beaty, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Kevin Groen, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Alexander O Pasternak, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Georgios Pollakis, Department of Clinical Infection, Microbiology and Immunology (CIMI), University of Liverpool, Liverpool, 8 West Derby Street, United Kingdom.
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  • Monique Vink, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Ellen M Westerhout, Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Mohamed Hamdi, Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Margreet Bakker, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Boas van der Putten, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Suzanne Jurriaans, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Jan H Prins, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Rienk Jeeninga, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Adri A M Thomas, Department Developmental Biology, Faculty Beta-Science, Utrecht, Padualaan 8, 3584, CH, the Netherlands.
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  • Dave Speijer, Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.
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  • Ben Berkhout, Department of Medical Microbiology, Laboratory of Experimental Virology, Amsterdam University Medical Centers, Amsterdam, Meibergdreef 15, 1105AZ, the Netherlands.

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.

OriginalsprogEngelsk
TidsskriftEBioMedicine
Vol/bind42
Sider (fra-til)97-108
Antal sider12
DOI
StatusUdgivet - 26 apr. 2019
Eksternt udgivetJa

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