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

Abstract

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.

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

“…Identifying novel pathways or effector molecules involved in latency maintenance and reversal is appealing ( Figure 1 ). New findings regarding pathways related to cell longevity and immune-cell differentiation or regulatory kinase pathways and their control over transcription factors and cytokine expression during HIV latency are crucial [ 78 , 79 , 112 ]. Therefore, the involvement of pro- and anti-apoptotic proteins and their interactions with viral proteins in immune cells during latent HIV infection warrants further investigation.…”

“…The mammalian target of rapamycin (mTOR) protein is a serine/threonine protein kinase that belongs to the PI3K-related kinase family and is associated with a wide range of cellular processes such as cell proliferation, motility, growth, and survival, as well as protein synthesis and gene transcription. The interactions between dendritic cells and T cells through cell surface receptors/ligands, which activate PI3K-Akt-mTOR signaling by triggering dephosphorylation of proteins downstream of the Akt signaling pathway [ 112 ], play an important role in HIV latency reversal. However, such activation does not increase the expression/activity of nuclear transcription factors, such as NF-κB.…”

“…However, such activation does not increase the expression/activity of nuclear transcription factors, such as NF-κB. Even blockade of c-Fos and c-Jun transcription factors, which directly bind to HIV-1 LTR promoter regions, does not affect dendritic cell contact-mediated latency reversal [ 112 ]. Also, HIV Tat drives latent provirus to an active virus-producing state by recruiting pTEFb complex and interacting with the viral mRNA hairpin in the HIV promoter region [ 113 ].…”

Modulation of mTORC1 Signaling Pathway by HIV-1

“…In an effort to optimize the "shock and kill" approach, recent findings revealed that interaction of infected CD4+ T cells with DC could activate latent HIV-1 [99]. The contact with dendritic cells also activates the PI3K-Akt-mTOR pathway in CD4+ T cells and contributes to HIV-1 purge.…”

Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

“…Although the incorporation of antigen in DC-mediated LR has been underexplored, Marini et al successfully utilized iDCs loaded with SEB superantigen for reactivation of HIV-1 in in vitro-infected CD4 + T cell lines [221]. Furthermore, van Montfort and colleagues determined that iDCs in combination with TCR stimulation more efficiently reversed latency in primary HIV-infected cells from aviremic individuals than TCR activation alone, a phenomenon that was dependent on PI3K-Akt-mTOR pathway activation [228]. Finally, a study investigating the latency activation potential of various DC subsets demonstrated that tissue-resident and blood-derived myeloid DCs reactivated virus in vitro from latently infected effector T cells with different efficiencies [229].…”