• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations
【24h】

Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations

机译：由于逃逸突变的优势，需要广泛的CTL反应来清除潜在的HIV-1

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

抗逆转录病毒疗法不能治愈HIV-1感染：尽管接受了药物治疗，但大部分患者体内仍有大量处于休眠状态的这种病毒，即存在病毒库。对从30位被HIV-1感染的患者(他们持续接受抗逆转录病毒治疗至少两年时间并且血浆中的HIV-1RNA一直保持在检测不到的水平)分离出的免疫细胞所做的这项研究显示，这些病毒库以具有"细胞毒性T-淋巴细胞逃避突变"的病毒为主导。该发现表明，治疗性疫苗设计的未来方向也许需要关注怎样提升大范围的"细胞毒性T-淋巴细胞反应"。%Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir, primarily in resting memory CD4~+ T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed5 and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (＞98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.
机译：抗逆转录病毒疗法不能治愈HIV-1感染：尽管接受了药物治疗，但大部分患者体内仍有大量处于休眠状态的这种病毒，即存在病毒库。对从30位被HIV-1感染的患者(他们持续接受抗逆转录病毒治疗至少两年时间并且血浆中的HIV-1RNA一直保持在检测不到的水平)分离出的免疫细胞所做的这项研究显示，这些病毒库以具有"细胞毒性T-淋巴细胞逃避突变"的病毒为主导。该发现表明，治疗性疫苗设计的未来方向也许需要关注怎样提升大范围的"细胞毒性T-淋巴细胞反应"。%Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir, primarily in resting memory CD4~+ T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed5 and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (＞98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.

著录项

  • 来源
    《Nature》 |2015年第7534期|381-385a3a5|共7页
  • 作者

    Kai Deng; Mihaela Pertea; Anthony Rongvaux; Leyao Wang; Christine M. Durand; Gabriel Ghiaur; Jun Lai; Holly L. McHugh; Haiping Hao; Hao Zhang; Joseph B. Margolick; Cagan Gurer; Andrew J. Murphy; David M. Valenzuela; George D. Yancopoulos; Steven G. Deeks; Till Strowig; Priti Kumar; Janet D. Siliciano; Steven L. Salzberg; Richard A. Flavell; Liang Shan; Robert F. Siliciano;

  • 作者单位

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA,Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Deep Sequencing and Microarray Core, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA;

    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA;

    Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA;

    Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA;

    Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA;

    Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA;

    Department of Medicine, University of California, San Francisco, San Francisco, California 94110, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA,Howard Hughes Medical Institute, Baltimore, Maryland 21205, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号