MiRNA-103 downmodulates CCR5 expression reducing human immunodeficiency virus type-1 entry and impacting latency establishment in CD4+ T cells
Nicolas Bellini,
Robert Lodge,
Tram N.Q. Pham,
Jaspreet Jain,
Thomas T. Murooka,
Alon Herschhorn,
Nicole F. Bernard,
Jean-Pierre Routy,
Cécile L. Tremblay,
Éric A. Cohen
Affiliations
Nicolas Bellini
Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
Robert Lodge
Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada
Tram N.Q. Pham
Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
Jaspreet Jain
Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada
Thomas T. Murooka
Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
Alon Herschhorn
Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Nicole F. Bernard
Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada; Research Institute of the McGill University Health Centre Montreal, Montreal, QC, Canada
Jean-Pierre Routy
Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada; Research Institute of the McGill University Health Centre Montreal, Montreal, QC, Canada
Cécile L. Tremblay
Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
Éric A. Cohen
Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada; Corresponding author
Summary: Activated-to-memory transitioning CD4+ T cells display elevated expression of the HIV-1 co-receptor CCR5 and are more prone to HIV-1 latent infection. Here, we show that p53-regulated miRNA-103 downmodulates CCR5 levels in CD4+ T lymphocytes. We reveal that miRNA-103 mimics, as well as Nutlin-3, an inhibitor of Mdm2-mediated p53 degradation, decrease CCR5-dependent HIV-1 infection. Using a dual-reporter virus, we subsequently validate that in transitioning CD4+ T cells, Nutlin-3 treatment decreases the frequency of both productively and latently infected cells via upregulation of miRNA-103. Importantly, we provide evidence that CD4+ T cells from HIV-1 elite controllers express less CCR5 than those from antiretroviral therapy-naïve progressors, an effect linked to a significant increase in miRNA-103 levels. By contributing to the control of CCR5 expression in CD4+ T cells, miRNA-103 is likely to play a key role in countering the establishment of latent HIV-1 reservoirs in vivo.