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

doi:10.1016/j.isci.2022.105234

MiRNA-103 downmodulates CCR5 expression reducing human immunodeficiency virus type-1 entry and impacting latency establishment in CD4⁺ T cells

iScience. 2022 Sep 28;25(10):105234. doi: 10.1016/j.isci.2022.105234. eCollection 2022 Oct 21.

Authors

Nicolas Bellini^{1

2}, Robert Lodge¹, Tram N Q Pham^{1

2}, Jaspreet Jain¹, Thomas T Murooka³, Alon Herschhorn⁴, Nicole F Bernard^{5

6}, Jean-Pierre Routy^{5

6}, Cécile L Tremblay^{7

2}, Éric A Cohen^{1

2}

Affiliations

¹ Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada.
² Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
³ Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
⁴ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁵ Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.
⁶ Research Institute of the McGill University Health Centre Montreal, Montreal, QC, Canada.
⁷ Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.

Abstract

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.

Keywords: Biological sciences; immunology; molecular biology.