IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques

Justin Harper, Nicolas Huot, Luca Micci, Gregory Tharp, Colin King, Philippe Rascle, Neeta Shenvi, Hong Wang, Cristin Galardi, Amit A. Upadhyay, Francois Villinger, Jeffrey Lifson, Guido Silvestri, Kirk Easley, Beatrice Jacquelin, Steven Bosinger, Michaela Müller-Trutwin and Mirko Paiardini ()
Additional contact information
Justin Harper: Emory University
Nicolas Huot: Inflammation et Persistance
Luca Micci: Emory University
Gregory Tharp: Emory University
Colin King: Emory University
Philippe Rascle: Inflammation et Persistance
Neeta Shenvi: Emory University
Hong Wang: Emory University
Cristin Galardi: University of North Carolina at Chapel Hill
Amit A. Upadhyay: Emory University
Francois Villinger: University of Louisiana at Lafayette
Jeffrey Lifson: Frederick National Laboratory for Cancer Research
Guido Silvestri: Emory University
Kirk Easley: Emory University
Beatrice Jacquelin: Inflammation et Persistance
Steven Bosinger: Emory University
Michaela Müller-Trutwin: Inflammation et Persistance
Mirko Paiardini: Emory University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/clowCD16+) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/clowCD16+ natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues.

Date: 2021
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DOI: 10.1038/s41467-021-23189-7

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