Bo Sun, Kelly A S da Costa, Aljawharah Alrubayyi, Jonida Kokici, Natasha Fisher-Pearson, Noshin Hussain, Stefano D'Anna, Lorenzo Piermatteo, Romina Salpini, Valentina Svicher, Stephanie Kucykowicz, Indrajit Ghosh, Fiona Burns, Sabine Kinloch, Pedro Simoes, Sanjay Bhagani, Patrick T F Kennedy, Mala K Maini, Rachael Bashford-Rogers, Upkar S Gill, Dimitra Peppa
{"title":"艾滋病病毒/乙型肝炎病毒联合感染重塑了免疫格局和自然杀伤细胞 ADCC 功能反应。","authors":"Bo Sun, Kelly A S da Costa, Aljawharah Alrubayyi, Jonida Kokici, Natasha Fisher-Pearson, Noshin Hussain, Stefano D'Anna, Lorenzo Piermatteo, Romina Salpini, Valentina Svicher, Stephanie Kucykowicz, Indrajit Ghosh, Fiona Burns, Sabine Kinloch, Pedro Simoes, Sanjay Bhagani, Patrick T F Kennedy, Mala K Maini, Rachael Bashford-Rogers, Upkar S Gill, Dimitra Peppa","doi":"10.1097/HEP.0000000000000877","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>HBV and HIV coinfection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to immune dysregulation including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. Here we used high-throughput single-cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV coinfection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets that can be therapeutically harnessed.</p><p><strong>Approach and results: </strong>Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV coinfection was characterized by an over-representation of adaptive, KLRC2 -expressing NK cells, including a higher abundance of a chemokine-enriched ( CCL3/CCL4 ) adaptive cluster. The NK cell remodeling in HIV/HBV coinfection was reflected in enriched activation pathways, including CD3ζ phosphorylation and ZAP-70 translocation that can mediate stronger antibody-dependent cellular cytotoxicity responses and a bias toward chemokine/cytokine signaling. By contrast, HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of \"exhaustion\" with higher circulating levels of HBsAg. Phenotypic alterations in the NK cell pool in coinfection were consistent with increased \"adaptiveness\" and better capacity for antibody-dependent cellular cytotoxicity compared to HBV mono-infection. Overall, an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort.</p><p><strong>Conclusions: </strong>This study provides new insights into the differential signature and functional profile of NK cells in HBV and HIV/HBV coinfection, highlighting pathways that can be manipulated to tailor NK cell-focused approaches to advance HBV cure strategies in different patient groups.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"HIV/HBV coinfection remodels the immune landscape and natural killer cell ADCC functional responses.\",\"authors\":\"Bo Sun, Kelly A S da Costa, Aljawharah Alrubayyi, Jonida Kokici, Natasha Fisher-Pearson, Noshin Hussain, Stefano D'Anna, Lorenzo Piermatteo, Romina Salpini, Valentina Svicher, Stephanie Kucykowicz, Indrajit Ghosh, Fiona Burns, Sabine Kinloch, Pedro Simoes, Sanjay Bhagani, Patrick T F Kennedy, Mala K Maini, Rachael Bashford-Rogers, Upkar S Gill, Dimitra Peppa\",\"doi\":\"10.1097/HEP.0000000000000877\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>HBV and HIV coinfection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to immune dysregulation including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. Here we used high-throughput single-cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV coinfection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets that can be therapeutically harnessed.</p><p><strong>Approach and results: </strong>Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV coinfection was characterized by an over-representation of adaptive, KLRC2 -expressing NK cells, including a higher abundance of a chemokine-enriched ( CCL3/CCL4 ) adaptive cluster. The NK cell remodeling in HIV/HBV coinfection was reflected in enriched activation pathways, including CD3ζ phosphorylation and ZAP-70 translocation that can mediate stronger antibody-dependent cellular cytotoxicity responses and a bias toward chemokine/cytokine signaling. By contrast, HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of \\\"exhaustion\\\" with higher circulating levels of HBsAg. Phenotypic alterations in the NK cell pool in coinfection were consistent with increased \\\"adaptiveness\\\" and better capacity for antibody-dependent cellular cytotoxicity compared to HBV mono-infection. Overall, an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort.</p><p><strong>Conclusions: </strong>This study provides new insights into the differential signature and functional profile of NK cells in HBV and HIV/HBV coinfection, highlighting pathways that can be manipulated to tailor NK cell-focused approaches to advance HBV cure strategies in different patient groups.</p>\",\"PeriodicalId\":177,\"journal\":{\"name\":\"Hepatology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.9000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hepatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/HEP.0000000000000877\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/4/30 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hepatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/HEP.0000000000000877","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/4/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:HBV 和 HIV 合并感染是全球的常见病,发病率和死亡率都很高。这两种病毒都会导致免疫失调,包括 NK 细胞的变化,NK 细胞是抗病毒防御的关键组成部分,也是 HBV 治疗策略的一个有希望的靶点。在这里,我们利用高通量单细胞分析来探索单株 HBV 感染者和接受抗病毒治疗的 HIV/HBV 合并感染者的免疫细胞情况,重点是确定可用于治疗的 NK 细胞亚群的独特特征:我们的数据显示,NK细胞的转录程序存在显著差异。HIV/HBV合并感染的特点是表达KLRC2的适应性NK细胞比例过高,包括富含趋化因子(CCL3/CCL4)的适应性集群数量较高。HIV/HBV联合感染中的NK细胞重塑反映在丰富的活化途径上,包括CD3ζ磷酸化和ZAP-70转位,它们可以介导更强的ADCC反应,并偏向于趋化因子/细胞因子信号转导。相比之下,单一 HBV 感染会对 NK 细胞产生更强的细胞毒性,而且 "衰竭 "特征更为显著,循环中的 HBsAg 水平更高。与单一 HBV 感染相比,合并感染时 NK 细胞池的表型变化与 "适应性 "增强和 ADCC 能力提高相一致。总体而言,在我们的队列中,适应性 NK 细胞特征与 HBsAg 和 HBV-RNA 循环水平成反比:这项研究提供了有关 HBV 和 HIV/HBV 合并感染中 NK 细胞特征和功能特征差异的新见解,强调了可用于定制 NK 细胞治疗方法的途径,以推进不同患者群体的 HBV 治愈策略。
HIV/HBV coinfection remodels the immune landscape and natural killer cell ADCC functional responses.
Background and aims: HBV and HIV coinfection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to immune dysregulation including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. Here we used high-throughput single-cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV coinfection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets that can be therapeutically harnessed.
Approach and results: Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV coinfection was characterized by an over-representation of adaptive, KLRC2 -expressing NK cells, including a higher abundance of a chemokine-enriched ( CCL3/CCL4 ) adaptive cluster. The NK cell remodeling in HIV/HBV coinfection was reflected in enriched activation pathways, including CD3ζ phosphorylation and ZAP-70 translocation that can mediate stronger antibody-dependent cellular cytotoxicity responses and a bias toward chemokine/cytokine signaling. By contrast, HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of "exhaustion" with higher circulating levels of HBsAg. Phenotypic alterations in the NK cell pool in coinfection were consistent with increased "adaptiveness" and better capacity for antibody-dependent cellular cytotoxicity compared to HBV mono-infection. Overall, an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort.
Conclusions: This study provides new insights into the differential signature and functional profile of NK cells in HBV and HIV/HBV coinfection, highlighting pathways that can be manipulated to tailor NK cell-focused approaches to advance HBV cure strategies in different patient groups.
期刊介绍:
HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.