Natural killer cell phenotype is altered in HIV-exposed seronegative women (pdf)

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Natural killer cell phenotype is altered in HIV-exposed seronegative women

PLOS ONE RESEARCH ARTICLE Natural killer cell phenotype is altered in HIVexposed seronegative women Nancy Q. Zhao1,2☯, Elena Vendrame ID1☯, Anne-Maud Ferreira3, Christof Seiler3, Thanmayi Ranganath ID1, Michel Alary ID4, Annie-Claude Labbé5, Fernand Guédou6, Johanne Poudrier7, Susan Holmes3, Michel Roger7*, Catherine A. Blish1,2,8* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Medicine, Division of Infection Diseases and Geographic Medicine, Stanford University, Stanford, CA, United States of America, 2 Immunology Program, Stanford University, Stanford, CA, United States of America, 3 Department of Statistics, Stanford University, Stanford, CA, United States of America, 4 Centre de Recherche du CHU de Québec–Université Laval, Québec, Canada, Département de Médecine Sociale et Préventive, Université Laval, Québec, Canada, Institut National de Santé Publique du Québec, Québec, Canada, 5 Département de Microbiologie, Infectiologie et Immunologie de l‘Université de Montréal, Montréal, Canada, Service de maladies infectieuses et microbiologie, Hôpital Maisonneuve-Rosemont, Montréal, Canada, 6 Dispensaire IST, Cotonou, Bénin, 7 Laboratoire d’Immunogénétique, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Canada, Département de Microbiologie, Infectiologie et Immunologie de l‘Université de Montréal, Montréal, Canada, 8 Chan Zuckerberg Biohub, San Francisco, CA, United States of America ☯ These authors contributed equally to this work. * (CAB); (MR) OPEN ACCESS Citation: Zhao NQ, Vendrame E, Ferreira A-M, Seiler C, Ranganath T, Alary M, et al. (2020) Natural killer cell phenotype is altered in HIVexposed seronegative women. PLoS ONE 15(9): e0238347. https://doi.org/10.1371/journal. pone.0238347 Editor: Aftab A. Ansari, Emory University School of Medicine, UNITED STATES Received: June 20, 2020 Accepted: August 14, 2020 Published: September 1, 2020 Copyright: © 2020 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data supporting this publication is available at ImmPort (https:// www.immport.org) under study accession SDY1647. Funding: This work was supported by: NIH Ruth L. Kirschstein Institutional National Research Service Award T32 AI007502 and TL1 TR001084 (EV), NIH/NIAID K08 AI138640 (EV), ITI/Bill & Melinda Gates Foundation Pilot Grant (CAB), NIH/NIAID DP2 AI112193 (CAB), NIH/NIDA Avant Garde Award for HIV Research DP1 DA046089 (CAB), Abstract Highly exposed seronegative (HESN) individuals present a unique setting to study mechanisms of protection against HIV acquisition. As natural killer (NK) cell activation and function have been implicated as a correlate of protection in HESN individuals, we sought to better understand the features of NK cells that may confer protection. We used mass cytometry to phenotypically profile NK cells from a cohort of Beninese sex workers and healthy controls. We found that NK cells from HESN women had increased expression of NKG2A, NKp30 and LILRB1, as well as the Fc receptor CD16, and decreased expression of DNAM-1, CD94, Siglec-7, and NKp44. Using functional assessments of NK cells from healthy donors against autologous HIV-infected CD4+ T cells, we observed that NKp30+ and Siglec-7+ cells had improved functional activity. Further, we found that NK cells from HESN women trended towards increased antibody-dependent cellular cytotoxicity (ADCC) activity; this activity correlated with increased CD16 expression. Overall, we identify features of NK cells in HESN women that may contribute to protection from HIV infection. Follow up studies with larger cohorts are warranted to confirm these findings. Introduction Human immunodeficiency virus (HIV) remains a significant health problem, with 37.9 million people still living with HIV at the end of 2018 and an estimated 1.7 million new infections every year (www.who.int). Many advances have been made in the treatment and prevention of HIV. The advent of antiretroviral therapy (ART) has transformed HIV from a universally fatal PLOS ONE | https://doi.org/10.1371/journal.pone.0238347 September 1, 2020 1 / 17 PLOS ONE Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases (CAB), Grant # PJT-148529 from the Canadian Institutes of Health Research and by the Réseau SIDA from the Fonds de Recherche du Québec en Santé (MR). NQZ was supported by a National Science Scholarship from the Agency of Science, Technology and Research (A� STAR) Singapore. CAB is an investigator of the Chan Zuckerberg Biohub. Competing interests: The authors have declared that no competing interests exist. Natural killer cells in highly exposed seronegative women disease into a manageable disease with near-normal life expectancy, and pre-exposure prophylaxis (PrEP) with antiretrovirals is highly effective in preventing HIV acquisition. However, ART use for treatment and prevention has serious limitations, including cost, side-effects and accessibility, making novel HIV prevention and treatment strategies desperately needed to halt the epidemic. Highly HIV-exposed seronegative (HESN) individuals are a unique population who show a natural resistance to HIV acquisition despite repeated exposures. The study of these individuals has identified multiple correlates of protection from HIV acquisition, and a better understanding of these correlates could facilitate the design of innovative preventive measures and vaccine approaches. Natural killer (NK) cells are able to quickly and rapidly respond to viral infections and their function is determined by the combinatorial signaling of inhibitory and activating receptors expressed on the cell surface [1]. NK cells have been implicated in early immune responses to HIV infection (reviewed in [2]). Although traditionally this was thought to be a non-antigenspecific response, recent data have shown that NK cells may also be capable of generating memory-like responses to viral antigens, including HIV [3–7]. NK cells expand during the early stages of HIV infection [8,9], and respond to HIV in vivo and in vitro [10–13]. NK cellmediated antibody-dependent cytotoxicity (ADCC) has also been linked to slower disease progression [14,15] and, when combined with specific human leukocyte antigen (HLA) alleles, certain killer immunoglobulin-like receptors (KIR) were associated with slower disease progression [16–18], and elite control of HIV [19]. Increasing evidence suggests that specific NK cell features can also confer protection from HIV acquisition. Genetic studies revealed that the presence of specific KIR/HLA combinations may contribute to protection of HESN from HIV infection via intravenous or sexual routes [20–26]. Additionally, a (...truncated)