ART Plus Combination Immunotherapy Expands Natural Killer Cells That Facilitate Control of HIV

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Yerkes National Primate Research Center researchers in collaboration with Institut Pasteur have determined a combination immunotherapy of Interleukin-21 (IL-21) and interferon alpha (IFNa) is effective in generating highly functional natural killer (NK) cells that can help control and reduce simian immunodeficiency virus (SIV) in animal models. This finding is key for controlling HIV/AIDS, which impacts 38 million people worldwide, as antiviral therapy (ART) alone, while capable of reducing viremia to undetectable levels, is not curative and is hampered by issues such as cost, adherence, and social stigma. The results of this study were published in Nature Communications on May 17th, 2021.

In most animal models, infection with SIV progress to AIDS and generates natural killer (NK) cells with impaired functionality, unlike in animal models of SIV that do not progress to AIDS (Huot et al., Nat Commun, 2021). In the study, which is published online today in Nature Communications, researchers worked with 16 animal models that were receiving suppressive ART. The researchers compared the ability of animal models that were also treated with IL-21 and IFNa to those that had not received the combination immunotherapy to evaluate how the ART plus combination immunotherapy affected the amount of virus in tissue.  

Our results indicate the ART plus combo-treated rhesus animal models showed enhanced antiviral NK cell responses that promoted the clearance of cells harboring virus able to replicate in lymph nodes (LN), which are known for facilitating the virus’ persistence,” says first author Justin Harper, PhD together with Nicolas Huot, researcher in the HIV, Inflammation and Persistence Unit at the Institut Pasteur. “Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV,” Harper continues. Harper is a senior Research Specialist and the Lab Manager of the Paiardini laboratory. 

HIV treatment has historically focused on the role of T cells in immunity. “This proof-of-concept study in animal models which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activity can contribute to controlling the virus,” says Mirko Paiardini, PhD. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission, and, ultimately, reducing the burden HIV is to individuals, families and the world,” he adds. Paiardini is an associate professor of Pathology and Laboratory Medicine at Emory University and a researcher at Yerkes.

Combining ART with this new immunotherapy has prolonged viral control after stopping ART. The results of this study provide evidence of the essential role that mature NK cells can play in the ability to reduce viral reservoirs, constituting an important step in the search for a strategy toward HIV remission” concludes Michaela Müller-Trutwin, head of the HIV, Inflammation and Persistence Unit at the Institut Pasteur.

The research reported in this release is supported in part by the by the Yerkes National Primate Research Center base grant from the NIH Office of the Director, Office of Research Infrastructure Programs. The National Institute of Allergy and Infectious Diseases, National Center for Research Resources, and National Cancer Institute provided additional funding as did the French National Agency of Research on AIDS and Viral Hepatitis (ANRS) and the Fondation J. Beytout.


IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques, Nature Communications, 17 mai 2021

Justin Harper1,11, Nicolas Huot2,11, Luca Micci1, Gregory Tharp3, Colin King1, Philippe Rascle2,4, Neeta Shenvi5, Hong Wang1, Cristin Galardi6,7, Amit A Upadhyay3, Francois Villinger8, Jeffrey Lifson9, Guido Silvestri1,10, Kirk Easley5, Beatrice Jacquelin2, Steven Bosinger1,3,10, Michaela Müller-Trutwin2,12, Mirko Paiardini*1,10,12

1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
2Institut Pasteur, Unité HIV, Inflammation et Persistance, Paris, France.
3Nonhuman Primate Genomics Core, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
4Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
5Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
6UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
7HIV Discovery, ViiV Healthcare, Research Triangle Park, NC, USA.
8Department of Biology, New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA.
9AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
10Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

11These authors contributed equally.
12 These authors contributed equally.

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