Date Published: May 22, 2019
Publisher: Public Library of Science
Author(s): Matthew Gagne, Daniel Michaels, Gillian M. Schiralli Lester, Suryaram Gummuluru, Wilson W. Wong, Andrew J. Henderson, Ronald Swanstrom.
A major barrier to curing HIV-1 is the long-lived latent reservoir that supports re-emergence of HIV-1 upon treatment interruption. Targeting this reservoir will require mechanistic insights into the establishment and maintenance of HIV-1 latency. Whether T cell signaling at the time of HIV-1 infection influences productive replication or latency is not fully understood. We used a panel of chimeric antigen receptors (CARs) with different ligand binding affinities to induce a range of signaling strengths to model differential T cell receptor signaling at the time of HIV-1 infection. Stimulation of T cell lines or primary CD4+ T cells expressing chimeric antigen receptors supported HIV-1 infection regardless of affinity for ligand; however, only signaling by the highest affinity receptor facilitated HIV-1 expression. Activation of chimeric antigen receptors that had intermediate and low binding affinities did not support provirus transcription, suggesting that a minimal signal is required for optimal HIV-1 expression. In addition, strong signaling at the time of infection produced a latent population that was readily inducible, whereas latent cells generated in response to weaker signals were not easily reversed. Chromatin immunoprecipitation showed HIV-1 transcription was limited by transcriptional elongation and that robust signaling decreased the presence of negative elongation factor, a pausing factor, by more than 80%. These studies demonstrate that T cell signaling influences HIV-1 infection and the establishment of different subsets of latently infected cells, which may have implications for targeting the HIV-1 reservoir.
HIV-1 persists in a transcriptionally silent latent state in long-lived memory T cells. Although antiretroviral therapies (ART) suppress HIV-1 replication, interruption of treatment results in rapid viral rebound. Therefore, HIV-1 patients must remain on ART indefinitely, despite long-term side effects, development of treatment resistance, and viral-induced inflammation [1–3]. For this reason, one strategy currently being explored for cure efforts is “shock and kill,” in which latent HIV-1 is reactivated in conjunction with ART using latency-reversing agents (LRAs). Following reactivation, infected cells are predicted to be eliminated by HIV-specific immunity or virally induced apoptosis. However, clinical trials using LRAs have only minimally perturbed the size of the viral reservoir [4–6].
Previous studies suggest that cell signaling may be a key regulator of HIV-1 expression and latency. The latent reservoir is enriched for antigen specific T cells, including those that respond to CMV, HSV, tuberculosis, and HIV [21–25]. Furthermore, the use of superantigens during viral entry increases HIV-1 replication . Partial activation, cellular polarization, cell-to-cell contact, and/or infection of resting quiescent cells through perturbation have also been suggested to bias infections towards latency [11,27–31]. Therefore, the extent of cell activation is a key determinant in regulating the course of HIV-1 infection including the formation of the reservoir.