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

PLoS Pathogens

Ben Berkhout¹  Dave Speijer²  Rogier W. Sanders³  Rienk E. Jeeninga³  Georgios Pollakis³  Renée M. van der Sluis³  Thijs van Montfort³ 

[1] Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America;Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

关键词: T cells;    HIV-1;    Viral persistence;    latency;    Flow cytometry;    Enzyme-linked immunoassays;    Dendritic cells;    Transcription factors;    Antibodies;   

DOI  :  10.1371/journal.ppat.1003259

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY