Journal
CELL REPORTS
Volume 14, Issue 9, Pages 2100-2107Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.02.022
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Funding
- Spanish Ministry of Economy and Competitiveness [SAF2010-18388, SAF2013-44677-R, FIS PI12/00506]
- SPANISH AIDS Research Network [RD12/0017/0015]
- ISCIII-Subdireccion General de Evaluacion
- European Funding for Regional Development (FEDER)
- Bristol-Myers Squibb (BMS) [AI471-041]
- joined program of the Agence nationale de recherches sur le sida et les hepatites virales (ANRS) [2014-2]
- European FP7-HEALTH project HIT HIDDEN HIV
- Instituto de Salud Carlos III (MPY) [1371/12]
- NIH [AI 069501, A5214]
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HIV-1 post-integration latency inCD4+ lymphocytes is responsible for viral persistence despite treatment, but mechanisms involved in the establishment of latent viral reservoirs are not fully understood. We determined that both interleukin 2 (IL-2) and IL-7 induced SAMHD1 phosphorylation in T592, abrogating its antiviral activity. However, IL-7 caused a much more profound stimulatory effect on HIV-1 reverse transcription and integration than IL-2 that required chemokine co-stimulation. Both cytokines barely induced transcription due to low NF-kappa B induction, favoring the establishment of latent reservoirs. Effect of IL-7 on SAMHD1 phosphorylation was confirmed in IL-7-treated patients (ACTG 5214 study). Dasatinib-a tyrosine-kinase inhibitorblocked SAMHD1 phosphorylation induced by IL-2 and IL-7 and restored HIV-1 restriction. We propose that gc-cytokines play a major role in the reservoir establishment not only by driving homeostatic proliferation but also by increasing susceptibility of CD4+ lymphocytes to HIV-1 infection through SAMHD1 inactivation.
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