Dendritic Cell-induced Activation of Latent HIV-1 Provirus in Actively Proliferating Primary T Lymphocytes

Abstract

HIV-1 latency remains a formidable barrier towards virus eradication as therapeutic attempts to purge these reservoirs are so far unsuccessful. The pool of transcriptionally silent proviruses is established early in infection and persists for a lifetime, even when viral loads are suppressed below detection levels using anti-retroviral therapy. Upon therapy interruption the reservoir can re-establish systemic infection. Different cellular reservoirs that harbor latent provirus have been described. In this study we demonstrate that HIV-1 can also establish a silent integration in actively proliferating primary T lymphocytes. Co-culturing of these proliferating T lymphocytes with dendritic cells (DCs) activated the provirus from latency. Activation did not involve DC-mediated C-type lectin DC-SIGN signaling or TCR-stimulation but was mediated by DC-secreted component(s) and cell-cell interaction between DC and T lymphocyte that could be inhibited by blocking ICAM-1 dependent adhesion. These results imply that circulating DCs could purge HIV-1 from latency and re-initiate virus replication. Moreover, our data show that viral latency can be established early after infection and supports the idea that actively proliferating T lymphocytes with an effector phenotype contribute to the latent viral reservoir. Unraveling this physiologically relevant purging mechanism could provide useful information for the development of new therapeutic strategies that aim at the eradication of HIV-1 reservoirs. Combination therapy can suppress the viral load in HIV-1 infected individuals to undetectable levels, but does not lead to complete virus eradication. Even after many years of successful therapy the virus is still present in long-lived cells as a latently integrated provirus. HIV-1 can re-establish systemic infection from this reservoir when therapy stops. Purging attempts in patients have been unsuccessful and HIV-1 latency remains a formidable barrier to virus eradication. Different cellular reservoirs that harbor latent HIV-1 proviruses have been described to consist mainly of resting memory T lymphocytes. Yet how this reservoir in memory T lymphocytes is established is still unclear as infection of these cells is very inefficient. In this paper we demonstrate that HIV-1 can establish a latent provirus in activated effector T lymphocytes. We observed that for every virus producing cell there is at least one other cell harboring a latent provirus, illustrating that latent infections occur frequently. Proliferating T lymphocytes are generally short-lived and their contribution to the total cellular reservoir thus seems limited. However, these activated T lymphocytes can revert into resting memory T lymphocytes and become part of the long-lived viral reservoir.