Citation: Alsulami, K.; Dupuy, F.P.; Gilbert, L.; Messier-Peet, M.; Durand, M.; Tremblay, C.; Routy, J.-P.; Bruneau, J.; Baril, J.-G.; Trottier, B.; et al. The Frequency and Function of NKG2C + CD57 + Adaptive NK Cells in Cytomagalovirus Co-Infected People Living with HIV Decline with Duration of Antiretroviral Therapy. Viruses 2023, 15, 323. https:// doi.org/10.3390/v15020323 Academic Editors: Angela Kaida, Hélène C. F. Côté, Melanie Murray and Elizabeth King Received: 3 January 2023 Revised: 16 January 2023 Accepted: 19 January 2023 Published: 24 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). viruses Article The Frequency and Function of NKG2C + CD57 + Adaptive NK Cells in Cytomagalovirus Co-Infected People Living with HIV Decline with Duration of Antiretroviral Therapy Khlood Alsulami 1,2,3 , Franck P. Dupuy 1,3 , Louise Gilbert 1,3 , Marc Messier-Peet 4 , Madeleine Durand 4 , Cécile Tremblay 4,5 , Jean-Pierre Routy 1,3,6,7 , Julie Bruneau 4,8 , Jean-Guy Baril 9 , Benoit Trottier 9 and Nicole F. Bernard 1,2,3,7,10, * 1 Research Institute of the McGill University Health Centre (RI-MUHC), Glen Site, Bloc E, 1001 Decarie Blvd., Room EM3.3238, Montreal, QC H4A 3J1, Canada 2 Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada 3 Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada 4 Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada 5 Department of Microbiology Infectiology and Immunology, University of Montreal, Montreal, QC H3C 3J7, Canada 6 Division of Hematology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada 7 Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC H4A 3J1, Canada 8 Department of Family Medicine and Emergency Medicine, Université de Montréal, Montreal, QC H3X 0A9, Canada 9 Clinique de Médecine Urbaine du Quartier Latin, Montreal, QC H2L 4E9, Canada 10 Division of Clinical Immunology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada * Correspondence: nicole.bernard@mcgill.ca; Tel.: +1-(514)-934-1934 (ext. 44584); Fax: +1-(514)-933-1562 Abstract: Human cytomegalovirus (CMV) infection drives the expansion and differentiation of natural killer (NK) cells with adaptive-like features. We investigated whether age and time on antiretroviral therapy (ART) influenced adaptive NK cell frequency and functionality. Flow cytometry was used to evaluate the frequency of adaptive and conventional NK cells in 229 CMV + individuals of whom 170 were people living with HIV (PLWH). The frequency of these NK cell populations producing CD107a, CCL4, IFN-γ or TNF-α was determined following a 6-h antibody dependent (AD) stimulation. Though ART duration and age were correlated, longer time on ART was associated with a reduced frequency of adaptive NK cells. In general, the frequency and functionality of NK cells following AD stimulation did not differ significantly between treated CMV + PLWH and CMV + HIV - persons, suggesting that HIV infection, per se, did not compromise AD NK cell function. AD activation of adaptive NK cells from CMV + PLWH induced lower frequencies of IFN-γ or TNF-α secreting cells in older persons, when compared with younger persons. Keywords: people living with HIV (PLWH); HIV; CMV; NK cells; adaptive NK cells; aging 1. Introduction Human natural killer (NK) cells are involved in immune responses to viruses and tumor cells [1]. NK cells express germline encoded inhibitory and activating receptors that tune NK cell responses to target cells based on the latter’s expression of stress ligands, activating receptor ligands and loss of major histocompatibility complex (MHC) class I antigens, the ligands for inhibitory NK receptors (NKRs) [2]. NK cells, as part of the innate immune system, are primed to respond rapidly, before T and B cells can expand and differ- entiate into effector cells [3]. Mature NK cells comprise 10 to 15% of peripheral lymphocytes and can be divided into CD56 bright and CD56 dim subsets [4]. CD56 bright NK cells make up approximately 10% of circulating NK cells and are thought to be precursors of the more Viruses 2023, 15, 323. https://doi.org/10.3390/v15020323 https://www.mdpi.com/journal/viruses