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HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy
Journal of Virology ( IF 5.4 ) Pub Date : 2018-04-01 , DOI: 10.1128/jvi.02118-17
Sangeetha Satheesan 1, 2 , Haitang Li 2 , John C. Burnett 2 , Mayumi Takahashi 2 , Shasha Li 2 , Shiny Xiaqin Wu 3 , Timothy W. Synold 4 , John J. Rossi 1, 2 , Jiehua Zhou 2
Affiliation  

Although current combinatorial antiretroviral therapy (cART) is therapeutically effective in the majority of HIV patients, interruption of therapy can cause a rapid rebound in viremia, demonstrating the existence of a stable reservoir of latently infected cells. HIV latency is therefore considered a primary barrier to HIV eradication. Identifying, quantifying, and purging the HIV reservoir is crucial to effectively curing patients and relieving them from the lifelong requirement for therapy. Latently infected transformed cell models have been used to investigate HIV latency; however, these models cannot accurately represent the quiescent cellular environment of primary latently infected cells in vivo. For this reason, in vivo humanized murine models have been developed for screening antiviral agents, identifying latently infected T cells, and establishing treatment approaches for HIV research. Such models include humanized bone marrow/liver/thymus mice and SCID-hu-thy/liv mice, which are repopulated with human immune cells and implanted human tissues through laborious surgical manipulation. However, no one has utilized the human hematopoietic stem cell-engrafted NOD/SCID/IL2rγnull (NSG) model (hu-NSG) for this purpose. Therefore, in the present study, we used the HIV-infected hu-NSG mouse to recapitulate the key aspects of HIV infection and pathogenesis in vivo. Moreover, we evaluated the ability of HIV-infected human cells isolated from HIV-infected hu-NSG mice on suppressive cART to act as a latent HIV reservoir. Our results demonstrate that the hu-NSG model is an effective surgery-free in vivo system in which to efficiently evaluate HIV replication, antiretroviral therapy, latency and persistence, and eradication interventions.

IMPORTANCE HIV can establish a stably integrated, nonproductive state of infection at the level of individual cells, known as HIV latency, which is considered a primary barrier to curing HIV. A complete understanding of the establishment and role of HIV latency in vivo would greatly enhance attempts to develop novel HIV purging strategies. An ideal animal model for this purpose should be easy to work with, should have a shortened disease course so that efficacy testing can be completed in a reasonable time, and should have immune correlates that are easily translatable to humans. We therefore describe a novel application of the hematopoietic stem cell-transplanted humanized NSG model for dynamically testing antiretroviral treatment, supporting HIV infection, establishing HIV latency in vivo. The hu-NSG model could be a facile alternative to humanized bone marrow/liver/thymus or SCID-hu-thy/liv mice in which laborious surgical manipulation and time-consuming human cell reconstitution is required.



中文翻译:

在抑制性口服联合抗逆转录病毒疗法过程中,人性化的NSG小鼠模型中的HIV复制和潜伏期。

尽管当前的组合抗逆转录病毒疗法(cART)在大多数HIV患者中具有治疗效果,但中断治疗可导致病毒血症迅速反弹,这表明存在稳定的潜伏感染细胞库。因此,艾滋病毒潜伏期被认为是消除艾滋病毒的主要障碍。识别,量化和清除HIV储存库对于有效治愈患者并使他们摆脱终身治疗的需求至关重要。潜在感染的转化细胞模型已被用于调查HIV潜伏期。然而,这些模型不能准确地代表体内原发性潜伏感染细胞的静止细胞环境。因此,体内已开发出人源化的鼠模型来筛选抗病毒剂,鉴定潜伏感染的T细胞并建立HIV研究的治疗方法。此类模型包括人源化的骨髓/肝/胸腺小鼠和SCID-hu-thy / liv小鼠,它们通过人工免疫细胞重新植入人免疫细胞并植入人体组织。然而,没有人利用了人造血干细胞的移植后着床NOD / SCID /IL2rγ(NSG)用于此目的的模型(HU-NSG)。因此,在本研究中,我们使用感染了HIV的hu-NSG小鼠概括了体内HIV感染和发病机制的关键方面。此外,我们评估了抑制性cART上从HIV感染的hu-NSG小鼠中分离出的HIV感染的人类细胞作为潜在的HIV储库的能力。我们的结果表明,hu-NSG模型是一种有效的无手术体内系统,可有效评估HIV复制,抗逆转录病毒疗法,潜伏期和持久性以及根除干预措施。

重要信息HIV可以在单个细胞的水平上建立稳定整合的非生产性感染状态,称为HIV潜伏期,这被认为是治愈HIV的主要障碍。对体内HIV潜伏期的建立和作用的完全了解将极大地增强开发新颖的HIV清除策略的尝试。为此目的的理想动物模型应易于使用,应缩短病程,以便可以在合理的时间内完成功效测试,并应具有易于转化为人类的免疫相关性。因此,我们描述了造血干细胞移植的人源化NSG模型在动态测试抗逆转录病毒治疗,支持HIV感染,建立HIV潜伏期方面的新型应用体内。hu-NSG模型可以轻松替代人源化的骨髓/肝脏/胸腺或SCID-hu-thy / liv小鼠,因为这些小鼠需要费力的手术操作和费时的人体细胞重构。

更新日期:2018-03-15
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