Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.
{"title":"Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study.","authors":"Yunyu Mao, Qibin Liao, Youwei Zhu, Mingyuan Bi, Jun Zou, Nairong Zheng, Lingyan Zhu, Chen Zhao, Qing Liu, Li Liu, Jun Chen, Ling Gu, Zhuoqun Liu, Xinghao Pan, Ying Xue, Meiqi Feng, Tianlei Ying, Pingyu Zhou, Zhanshuai Wu, Jian Xiao, Renfang Zhang, Jing Leng, Yongtao Sun, Xiaoyan Zhang, Jianqing Xu","doi":"10.1038/s41421-024-00658-z","DOIUrl":"10.1038/s41421-024-00658-z","url":null,"abstract":"<p><p>Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1038/s41421-024-00679-8
Qian He, Qingning Yuan, Hong Shan, Canrong Wu, Yimin Gu, Kai Wu, Wen Hu, Yumu Zhang, Xinheng He, H Eric Xu, Li-Hua Zhao
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, Gi/o, and MCHR2 can only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.
黑色素浓缩激素(MCH)是一种环状神经肽,通过刺激 MCHR1 和 MCHR2 受体来调节食物摄入量、能量平衡和其他生理功能,这两种受体都是 A 类 G 蛋白偶联受体。MCHR1 主要与抑制性 G 蛋白 Gi/o 结合,而 MCHR2 只能与 Gq/11 结合。这里我们展示了 MCH 激活的 MCHR1 与 Gi 和 MCH 激活的 MCHR2 与 Gq 的冷冻电镜结构,其全局分辨率分别为 3.01 Å 和 2.40 Å。这些结构显示,当 MCH 与这两种受体结合时,其半胱氨酸介导的发夹环构型是一致的。在 MCH 的两个半胱氨酸之间,来自 LGRVY 核心基团的中央精氨酸深入跨膜袋,引发受体活化。结合突变和功能方面的见解,我们的发现阐明了配体识别和 MCH 受体激活的分子基础,并为靶向药物设计提供了结构基础。
{"title":"Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.","authors":"Qian He, Qingning Yuan, Hong Shan, Canrong Wu, Yimin Gu, Kai Wu, Wen Hu, Yumu Zhang, Xinheng He, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41421-024-00679-8","DOIUrl":"10.1038/s41421-024-00679-8","url":null,"abstract":"<p><p>Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, G<sub>i/o</sub>, and MCHR2 can only couple to G<sub>q/11</sub>. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with G<sub>i</sub> and MCH-activated MCHR2 with G<sub>q</sub> at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140851550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-04DOI: 10.1038/s41421-024-00671-2
Qingfeng Wang, Junfeng Ma, Yuxing Gong, Lifu Zhu, Huanyu Tang, Xingsheng Ye, Guannan Su, Fanfan Huang, Shiyao Tan, Xianbo Zuo, Yuan Gao, Peizeng Yang
Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet’s uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.
中性粒细胞是最丰富的免疫细胞,它们首先对血液循环中的损伤做出反应。尽管有关联证据表明,中性粒细胞的差异可能与炎症性疾病的性别特异性易感性有关,但机理上的联系仍然难以捉摸。在这里,我们以单细胞分辨率鉴定了正常和自身炎症条件下中性粒细胞组成的广泛性别特异性异质性。通过结合使用单细胞 RNA 测序分析、中性粒细胞特异性基因敲除和转移实验,我们发现了两种非常规(干扰素-α 反应性和 T 细胞调节性)中性粒细胞亚群的失调,这导致了自身炎症性白塞氏葡萄膜炎的男性偏向发病率、严重程度和不良预后。全基因组关联研究(GWAS)和外泌体研究显示,遗传因素和循环外泌体对非常规中性粒细胞亚群的负面影响导致男性易患病。总之,我们的研究结果确定了具有性别特异性的中性粒细胞亚群,并强调非常规中性粒细胞亚群是限制炎症性疾病的性别特异性治疗目标。
{"title":"Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet’s uveitis","authors":"Qingfeng Wang, Junfeng Ma, Yuxing Gong, Lifu Zhu, Huanyu Tang, Xingsheng Ye, Guannan Su, Fanfan Huang, Shiyao Tan, Xianbo Zuo, Yuan Gao, Peizeng Yang","doi":"10.1038/s41421-024-00671-2","DOIUrl":"https://doi.org/10.1038/s41421-024-00671-2","url":null,"abstract":"<p>Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet’s uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1038/s41421-024-00659-y
Bin Wei, Yuhui Fu, Xiuzhi Li, Fang Chen, Yiqing Zhang, Hanmo Chen, Mindan Tong, Linsen Li, Yi Pan, Shen Zhang, She Chen, Xiaoxia Liu, Qing Zhong
Macroautophagy is a process that cells engulf cytosolic materials by autophagosomes and deliver them to lysosomes for degradation. The biogenesis of autophagosomes requires ATG2 as a lipid transfer protein to transport lipids from existing membranes to phagophores. It is generally believed that endoplasmic reticulum is the main source for lipid supply of the forming autophagosomes; whether ATG2 can transfer lipids from other organelles to phagophores remains elusive. In this study, we identified a new ATG2A-binding protein, ANKFY1. Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux, which largely phenocopied ATG2A/B depletion. A pool of ANKFY1 co-localized with ATG2A between endosomes and phagophores and depletion of UVRAG, ANKFY1 or ATG2A/B led to reduction of PI3P distribution on phagophores. Purified recombinant ANKFY1 bound to PI3P on membrane through its FYVE domain and enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes. Therefore, we propose that ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. This finding implicates a new lipid source for ATG2A-mediated phagophore expansion, where endosomes donate PI3P and other lipids to phagophores via lipid transfer.
{"title":"ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores","authors":"Bin Wei, Yuhui Fu, Xiuzhi Li, Fang Chen, Yiqing Zhang, Hanmo Chen, Mindan Tong, Linsen Li, Yi Pan, Shen Zhang, She Chen, Xiaoxia Liu, Qing Zhong","doi":"10.1038/s41421-024-00659-y","DOIUrl":"https://doi.org/10.1038/s41421-024-00659-y","url":null,"abstract":"<p>Macroautophagy is a process that cells engulf cytosolic materials by autophagosomes and deliver them to lysosomes for degradation. The biogenesis of autophagosomes requires ATG2 as a lipid transfer protein to transport lipids from existing membranes to phagophores. It is generally believed that endoplasmic reticulum is the main source for lipid supply of the forming autophagosomes; whether ATG2 can transfer lipids from other organelles to phagophores remains elusive. In this study, we identified a new ATG2A-binding protein, ANKFY1. Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux, which largely phenocopied ATG2A/B depletion. A pool of ANKFY1 co-localized with ATG2A between endosomes and phagophores and depletion of UVRAG, ANKFY1 or ATG2A/B led to reduction of PI3P distribution on phagophores. Purified recombinant ANKFY1 bound to PI3P on membrane through its FYVE domain and enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes. Therefore, we propose that ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. This finding implicates a new lipid source for ATG2A-mediated phagophore expansion, where endosomes donate PI3P and other lipids to phagophores via lipid transfer.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140564504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}