小柯机器人

美国埃默里大学Mirko Paiardini研究组取得一项新突破。他们的研究显示在抗逆转录病毒疗法中断后，细胞程序性死亡蛋白1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）双重封锁诱导SIV激活，导致无法控制病毒反弹。论文在线发表于3月16日的《自然-医学》。

使用猿猴免疫缺陷病毒（SIV）感染并接受长期抗逆转录病毒疗法（ART）治疗的恒河猴，研究人员证明利用单克隆抗体PD-1、CTLA-4和双重CTLA-4 / PD-1免疫检查点封锁具有很好的耐受，这可被血液和淋巴结生物活性所证明。

双重阻断比单独PD-1阻断在增强T细胞循环和分化、扩大效应记忆T细胞，以及诱导血浆和外周血单核细胞中强大的病毒再激活方面明显更有效。在淋巴结中，双重CTLA-4 / PD-1阻断而非单独PD-1阻断降低了CD4 ⁺ T细胞中完整SIV-DNA的总和，以及B细胞卵泡中主要SIV-DNA和SIV-RNA在 ART期间病毒的持续性。

在ART或ART中断后的病毒控制期，所有测试过的干预措施均未增强SIV特异性CD8 ⁺ T细胞反应。因此，尽管在潜伏期CTLA-4 / PD-1封锁诱导了强大的逆转并降低了整合病毒的总体水平，但储库清除率仍不足以实现对病毒的控制。

这些结果表明，针对PD-1和/或CTLA-4的免疫检查点封锁方案，如果在患有持续无毒血症的HIV感染者中进行，那么在没有其他干预措施的情况下，不太可能诱导HIV缓解。

据了解，人类免疫缺陷病毒（HIV）的主要储存库是由静息CD4⁺记忆T细胞组成，它们通常表达免疫检查点受体PD-1和CTLA-4，其通过协同机制限制T细胞活化。

附：英文原文

Title: CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption

Author: Justin Harper, Shari Gordon, Chi Ngai Chan, Hong Wang, Emily Lindemuth, Cristin Galardi, Shane D. Falcinelli, Samuel L. M. Raines, Jenna L. Read, Kevin Nguyen, Colleen S McGary, Michael Nekorchuk, Kathleen Busman-Sahay, James Schawalder, Colin King, Maria Pino, Luca Micci, Barbara Cervasi, Sherrie Jean, Andrew Sanderson, Brian Johns, A. Alicia Koblansky, Heather Amrine-Madsen, Jeffrey Lifson, David M. Margolis, Guido Silvestri, Katharine J. Bar, David Favre, Jacob D. Estes, Mirko Paiardini

Issue&Volume: 2020-03-16

Abstract: The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.

DOI: 10.1038/s41591-020-0782-y

Source: https://www.nature.com/articles/s41591-020-0782-y

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex