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Title
NK cell-mediated viral control of SIV in sooty mangabey lymph nodes
Presenter
Michelle Y.-H. Lee
Authors
M.Y.-H. Lee1, W. Burgess2, N. Raju1, A.M. Metz1, N. Huot3, C. Petitdemange3, S. Liang4, K.A. Easley5, K. Busman-Sahay2, J.D. Estes2,6, F. Villinger7, R.K. Reeves8,9,10, M. Müller-Trutwin3, S.E. Bosinger1,11,12
Institutions
1Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, United States, 2Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States, 3Institut Pasteur, Unité HIV Inflammation and Persistance, Université de Paris Cité, Paris, France, 4Emory National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, United States, 5Emory University, Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, United States, 6Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States, 7New Iberia Research Center, University of Louisiana Lafayette, New Iberia, United States, 8Division of Innate and Comparative Immunology, Center for Human Systems Immunology, Duke University School of Medicine, Durham, United States, 9Duke University School of Medicine, Department of Surgery, Durham, United States, 10Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, United States, 11Emory NPRC Genomics Core Laboratory, Emory National Primate Research Center, Emory University, Atlanta, United States, 12Emory University School of Medicine, Department of Pathology and Laboratory Medicine, Atlanta, United States

BACKGROUND: Despite long-term combination antiretroviral therapy (cART), viral reservoir elimination in humans infected with HIV-1 remains elusive, due to the presence of latently infected cells and their sequestration in immunologic sanctuaries. During infections with HIV-1 and SIV of macaque species, CD4+ TFH cells in B cell follicles (BCF) of lymph nodes (LN) are a major reservoir for latent virus that remain largely inaccessible to CD8+ T cell-mediated killing. In prior work, we have demonstrated that BCFs in the SIV natural host African Green Monkey are generally virus free, and in vivo depletion of NK cells induces elevated plasma viremia and recrudescence of viral foci in lymph nodes. The goal of this study was to determine whether NK cell-mediated clearance of virus replication in LNs is a conserved feature of nonpathogenic SIV infection by analyzing NK cell depletion and viral dynamics in another SIV natural host, sooty mangabeys.
METHODS: We depleted NK cells from eight chronically SIVsmm infected sooty mangabeys by administration of recombinant anti-IL-15 (clone M111, 20 mg/kg, i.v.) and monitored plasma viral loads. NK cell function in blood and lymph nodes was assessed by flow cytometry and single-cell RNA-Seq.
RESULTS: Efficient depletion of NK cells was observed by 14 days post-infusion. Plasma levels of SIVsmm increased significantly from a mean of 2.06x105 copies/ml prior to depletion to 7.74x105 copies/ml at seven weeks post NK cell depletion (p < 0.0001 by linear trend test). A significant increase in cell-associated SIV RNA was observed in the LNs at day 42 post-infusion. To assess NK cell function, we sorted subpopulations of NK cells from LN based on CD16, CXCR5 and NKG2A expression and conducted single-cell RNA-Seq. Strikingly, within the CXCR5+ NKG2A+ population, we observed elevated expression of perforin, granzyme, and restriction factors.
CONCLUSIONS: This study demonstrated for the first time that NK cells contribute to control of viral replication in LNs of sooty mangabeys. This function of NK cells appears to be a general feature of nonpathogenic SIV infections. These findings further warrant the investigation of NK cell-based immunotherapies as part of cure and vaccine strategies for HIV-1.

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