Dendritic Cells Potently Purge Latent HIV-1 Beyond TCR-Stimulation, Activating the PI3K-Akt-mTOR Pathway

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. Funding Statement: RvdS, TvM, AOP, BB and REJ were supported by the Dutch Aidsfonds (Project numbers 2007028, 696 2008014, 2011020, 2012025, 2013021 and P-22602; (online at aidsfonds.nl/about/organisation)). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Informed written consent was obtained from all participants of this study, and the study was approved by the Medical Ethical Committee of the Academic Medical Center, Amsterdam. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.