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Immune clearance of highly pathogenic SIV infection

机译：高致病性SIV感染的免疫清除

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摘要

Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/ SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69-172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lenti-viral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.
机译：已确定的人类和猿猴免疫缺陷病毒（分别为HIV和SIV）已建立的感染是永久性的，即使是最有效的免疫反应和抗逆转录病毒疗法也只能控制（但不清楚）这些感染。维持这些感染的残留病毒是否易于清除是一个问题，对未来数百万艾滋病毒感染者的管理至关重要。我们最近报道说，接种表达SIV蛋白的恒河猴巨细胞病毒（RhCMV / SIV）载体的恒河猴（RM;猕猴）约有50％对高致病性菌株SIVmac239的感染表现出持久的，无毒的控制（参考文献5）。在这里我们表明，无论挑战的途径如何，RhCMV / SIV载体引发的免疫反应在可证实的淋巴和血源性病毒传播后均控制SIVmac239，并且具有复制能力的SIV在数个位置持续数周至数月。但是，随着时间的流逝，受保护的RM失去了SIV感染的迹象，显示出使用超灵敏测定法始终缺乏可测量的血浆或组织相关病毒，并且T细胞对不在疫苗中的SIV决定簇的反应性丧失。攻击后69-172周从RhCMV / SIV载体保护的RM尸检的组织进行的广泛超灵敏定量PCR和定量逆转录分析组织未检测到高于背景水平的SIV RNA或DNA序列，并且在这些样品中未检测到可复制的SIV通过对组织进行广泛的共培养分析或通过将6000万个血淋巴样细胞过继转移至幼稚RM中来获得RM。这些数据为病原性慢病毒感染的逐步清除提供了令人信服的证据，并表明某些慢病毒储库可能易受巨细胞病毒载体引发和维持的连续效应记忆T细胞介导的免疫监视的影响。

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  • 来源
    《Nature》 |2013年第7469期|100-104|共5页
  • 作者

    Scott G. Hansen; Michael PiatakJr; Abigail B. Ventura; Colette M. Hughes; Roxanne M. Gilbride; Julia C. Ford; Kelli Oswald; Rebecca Shoemaker; Yuan Li; Matthew S. Lewis; Awbrey N. Gilliam; Guangwu Xu; Nathan Whizin; Benjamin J. Burwitz; Shannon L. Planer; John M. Turner; Alfred W. Legasse; Michael K. Axthelm; Jay A. Nelson; Klaus Frueh; Jonah B. Sacha; Jacob D. Estes; Brandon F. Keele; Paul T. Edlefsen; Jeffrey D. Lifson; Louis J. Picker;

  • 作者单位

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;

    AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA;

    Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, 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);
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