Joana Dias, Giulia Fabozzi, Slim Fourati, Xuejun Chen, Cuiping Liu, David R. Ambrozak, Amy Ransier, Farida Laboune, Jianfei Hu, Wei Shi, Kylie March, Anna A. Maximova, Stephen D. Schmidt, Jakob Samsel, Chloe A. Talana, Keenan Ernste, Sung Hee Ko, Margaret E. Lucas, Pierce E. Radecki, Kristin L. Boswell, Yoshiaki Nishimura, John-Paul Todd, Malcolm A. Martin, Constantinos Petrovas, Eli A. Boritz, Nicole A. Doria-Rose, Daniel C. Douek, Rafick-Pierre Sékaly, Jeffrey D. Lifson, Mangaiarkarasi Asokan, Lucio Gama, John R. Mascola, Amarendra Pegu, Richard A. Koup
{"title":"在急性 SHIVAD8-EO 感染期间使用对 Fcγ 受体亲和力更强的抗 HIV-1 广泛中和单克隆抗体","authors":"Joana Dias, Giulia Fabozzi, Slim Fourati, Xuejun Chen, Cuiping Liu, David R. Ambrozak, Amy Ransier, Farida Laboune, Jianfei Hu, Wei Shi, Kylie March, Anna A. Maximova, Stephen D. Schmidt, Jakob Samsel, Chloe A. Talana, Keenan Ernste, Sung Hee Ko, Margaret E. Lucas, Pierce E. Radecki, Kristin L. Boswell, Yoshiaki Nishimura, John-Paul Todd, Malcolm A. Martin, Constantinos Petrovas, Eli A. Boritz, Nicole A. Doria-Rose, Daniel C. Douek, Rafick-Pierre Sékaly, Jeffrey D. Lifson, Mangaiarkarasi Asokan, Lucio Gama, John R. Mascola, Amarendra Pegu, Richard A. Koup","doi":"10.1038/s41467-024-51848-y","DOIUrl":null,"url":null,"abstract":"<p>Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIV<sub>AD8-EO</sub> infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8<sup>+</sup> CD69<sup>+</sup> T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":null,"pages":null},"PeriodicalIF":14.7000,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased affinity to Fcγ receptors during acute SHIVAD8-EO infection\",\"authors\":\"Joana Dias, Giulia Fabozzi, Slim Fourati, Xuejun Chen, Cuiping Liu, David R. Ambrozak, Amy Ransier, Farida Laboune, Jianfei Hu, Wei Shi, Kylie March, Anna A. Maximova, Stephen D. Schmidt, Jakob Samsel, Chloe A. Talana, Keenan Ernste, Sung Hee Ko, Margaret E. Lucas, Pierce E. Radecki, Kristin L. Boswell, Yoshiaki Nishimura, John-Paul Todd, Malcolm A. Martin, Constantinos Petrovas, Eli A. Boritz, Nicole A. Doria-Rose, Daniel C. Douek, Rafick-Pierre Sékaly, Jeffrey D. Lifson, Mangaiarkarasi Asokan, Lucio Gama, John R. Mascola, Amarendra Pegu, Richard A. Koup\",\"doi\":\"10.1038/s41467-024-51848-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. 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引用次数: 0
摘要
抗 HIV-1 广泛中和抗体(bNAbs)具有双重潜力,可分别通过其 Fab 和 Fc 结构域介导病毒中和与抗病毒效应器功能。迄今为止,体外增强 Fc 效应器功能的 bNAbs 只在慢性猿-HIV(SHIV)感染期间在 NHPs 中进行过测试。在这里,我们研究了在急性 SHIVAD8-EO 感染中使用野生型(WT)bNAbs 或携带 S239D/I332E/A330L (DEL) 突变的 bNAbs 的效果。病毒在血浆和淋巴结(LNs)中出现的时间会因 bNAb 处理而延迟,而且服用 DEL bNAb 的猴子比服用 WT bNAb 的猴子更早出现病毒,这与 DEL bNAb 从血浆中清除的速度更快是一致的。经 DEL bNAb 处理的猴子体内循环的病毒特异性 IFNγ 单产 CD8+ CD69+ T 细胞水平高于其他组别。在LN中,WT bNAbs均匀分布在滤泡区和滤泡外区,但DEL bNAbs主要分布在滤泡外区。在挑战后第 8 周,经 DEL bNAb 处理的猴子的 LN 单核细胞和 NK 细胞上调了促炎信号通路,而 LN T 细胞则通过 NF-κB 下调了 TNF 信号。总之,与FcγRs亲和力增强的bNAb会影响先天性和适应性细胞免疫,这可能是未来被动bNAb治疗策略中需要考虑的重要因素。
Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased affinity to Fcγ receptors during acute SHIVAD8-EO infection
Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIVAD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8+ CD69+ T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.