Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
Virol J. 2018 Dec 17;15(1):191. doi: 10.1186/s12985-018-1101-9.
The major obstacle to cure of HIV type-1 infection is the presence of the HIV reservoir, hidden from the immune system and insensitive to combined antiretroviral therapy (cART). Eradication approaches have been hindered by the difficulty for accurately monitoring its size in vivo, especially in the lymphoid organs. Humanized mouse models are a valuable tool for systematically assess the efficacy of therapeutic interventions in reducing the HIV reservoir. Nonetheless, persistence of the HIV reservoir over time, in the presence of cART, has yet to be analyzed in this in vivo model.
We found that the proviral DNA as well as the total DNA were very stable in the spleen and mesenteric lymph node irrespective of the length of cART. Notably, the amount of proviral DNA was very similar in the spleen and lymph node. Furthermore, we observed a correlation between the percentage of splenic human CD4+ T-cells with total HIV DNA, between the number of human CD38 + CD8+ T-cells in the spleen with the amount of integrated HIV DNA, and eventually between the hCD4/hCD8 ratio in the spleen with integrated as well as total HIV DNA implying that the CD8+ T cells influence the size of the HIV reservoir.
Here, we demonstrated the stability of this reservoir in humanized mice irrespective of the length of cART, confirming the relevancy of this model for HIV latency eradication investigations. Notably, we also found correlates between the frequency of CD4+ T-cells, their activation status and viral parameters, which were analogous to the ones in HIV-infected patients. Thus, hu-mice represent a very valuable HIV latency model.
治愈 HIV-1 感染的主要障碍是 HIV 储存库的存在，该储存库隐藏在免疫系统之外，并且对联合抗逆转录病毒疗法（cART）不敏感。由于难以准确监测体内其大小，尤其是在淋巴器官中，消除方法受到阻碍。人源化小鼠模型是系统评估治疗干预措施在减少 HIV 储存库方面的疗效的有价值工具。尽管如此，在存在 cART 的情况下，HIV 储存库随时间的持续存在尚未在该体内模型中进行分析。
我们发现，无论 cART 的长度如何，脾和肠系膜淋巴结中的前病毒 DNA 以及总 DNA 都非常稳定。值得注意的是，脾和淋巴结中的前病毒 DNA 量非常相似。此外，我们观察到脾中人类 CD4+T 细胞与总 HIV DNA 之间、脾中人类 CD38+CD8+T 细胞数量与整合 HIV DNA 量之间以及脾中 hCD4/hCD8 比值与整合以及总 HIV DNA 之间存在相关性，这表明 CD8+T 细胞影响 HIV 储存库的大小。
在这里，我们证明了该储存库在人源化小鼠中的稳定性，无论 cART 的长度如何，这证实了该模型对于 HIV 潜伏期消除研究的相关性。值得注意的是，我们还发现 CD4+T 细胞的频率、其激活状态和病毒参数之间存在相关性，这与 HIV 感染患者中的相关性类似。因此，hu-小鼠代表了一种非常有价值的 HIV 潜伏期模型。
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