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Dendritic Cells Potently Purge Latent HIV-1 in TCR-Activated Cells via the PI3K-Akt-mTOR Pathway: Implications for ‘Shock and Kill’ Strategies and Reservoir Analysis

40 Pages Posted: 8 Jun 2018 Publication Status: Review Complete

See all articles by Thijs van Montfort

Thijs van Montfort

University of Amsterdam - Laboratory of Experimental Virology

Renée van der Sluis

University of Amsterdam - Laboratory of Experimental Virology

Gilles Darcis

University of Amsterdam - Laboratory of Experimental Virology

Doyle Beaty

University of Amsterdam - Laboratory of Experimental Virology

Kevin Groen

University of Amsterdam - Laboratory of Experimental Virology

Alexander O. Pasternak

University of Amsterdam - Laboratory of Experimental Virology

Georgios Pollakis

University of Liverpool - Department of Clinical Infection, Microbiology and Immunology

Moniek Vink

University of Amsterdam - Laboratory of Experimental Virology

Ellen M. Westerhout

University of Amsterdam - Department of Oncogenomics

Mohamed Hamdi

University of Amsterdam - Department of Oncogenomics

Margreet Bakker

University of Amsterdam - Laboratory of Experimental Virology

Boas van der Putten

University of Amsterdam - Laboratory of Experimental Virology

Suzanne Jurriaans

University of Amsterdam - Laboratory of Experimental Virology

Jan Prins

University of Amsterdam - Department of Internal Medicine

Rienk Jeeninga

University of Amsterdam - Laboratory of Experimental Virology

Adri A.M. Thomas

Utrecht University - Division of Developmental Biology

Dave Speijer

University of Amsterdam - Department of Medical Biochemistry

Ben Berkhout

University of Amsterdam - Laboratory of Experimental Virology

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Abstract

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 demonstrate that TCR-stimulated effector T cells still frequently harbor latent HIV-1. Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with dendritic cells (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. This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.

Suggested Citation

van Montfort, Thijs and van der Sluis, Renée and Darcis, Gilles and Beaty, Doyle and Groen, Kevin and Pasternak, Alexander O. and Pollakis, Georgios and Vink, Moniek and Westerhout, Ellen M. and Hamdi, Mohamed and Bakker, Margreet and van der Putten, Boas and Jurriaans, Suzanne and Prins, Jan and Jeeninga, Rienk and Thomas, Adri A.M. and Speijer, Dave and Berkhout, Ben, Dendritic Cells Potently Purge Latent HIV-1 in TCR-Activated Cells via the PI3K-Akt-mTOR Pathway: Implications for ‘Shock and Kill’ Strategies and Reservoir Analysis (2018). Available at SSRN: https://ssrn.com/abstract=3192030 or http://dx.doi.org/10.2139/ssrn.3192030
This version of the paper has not been formally peer reviewed.

Thijs Van Montfort (Contact Author)

University of Amsterdam - Laboratory of Experimental Virology ( email )

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Renée Van der Sluis

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Gilles Darcis

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Doyle Beaty

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Kevin Groen

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Alexander O. Pasternak

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Georgios Pollakis

University of Liverpool - Department of Clinical Infection, Microbiology and Immunology

8 West Derby Street
The Ronald Ross Building
Liverpool, L69 7BE
United Kingdom

Moniek Vink

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Ellen M. Westerhout

University of Amsterdam - Department of Oncogenomics

Amsterdam, 1105 AZ
Netherlands

Mohamed Hamdi

University of Amsterdam - Department of Oncogenomics

Amsterdam, 1105 AZ
Netherlands

Margreet Bakker

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Boas Van der Putten

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Suzanne Jurriaans

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Jan Prins

University of Amsterdam - Department of Internal Medicine

Amsterdam, 1105 AZ
Netherlands

Rienk Jeeninga

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands

Adri A.M. Thomas

Utrecht University - Division of Developmental Biology

Padualaan 8
Utrecht, 3584 CH
Netherlands

Dave Speijer

University of Amsterdam - Department of Medical Biochemistry

Amsterdam, 1105 AZ
Netherlands

Ben Berkhout

University of Amsterdam - Laboratory of Experimental Virology

Meibergdreef 15
Amsterdam, 1105 AZ
Netherlands