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 K. Tharp, Colin T. King, Philippe Rascle, Neeta Shenvi, Hong Wang, Cristin M. Galardi, Amit A. Upadhyay, François Villinger, Jeffrey D. Lifson, Guido Silvestri, Kirk A. Easley, Béatrice Jacquelin, Steven E. Bosinger, Michaela Müller‐Trutwin, Mirko Paiardini
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/c low CD16 + ) 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/c low CD16 + 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.