HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency.
HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency.
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DOI：
10.1007/s13365-017-0604-2
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发表时间：
2018-04
影响因子：
3.2
通讯作者：
Cannon PM
中科院分区：
文献类型：
--
作者：
Llewellyn GN;Alvarez-Carbonell D;Chateau M;Karn J;Cannon PM
大多数关于 HIV 潜伏期的研究都集中在静息记忆 T 细胞的外周群体上，但大脑中也包含小胶质细胞、血管周围巨噬细胞和星形胶质细胞中独特的 HIV 感染细胞库。研究大脑中的 HIV 一直具有挑战性，因为很难从尸检样本中回收活细胞，而且由于 Vpx 的表达，SIV 感染的灵长类动物模型使用的病毒比 HIV 更具骨髓亲性。开发真实的小动物模型将极大地推进对这一重要病毒库的研究，并允许对艾滋病毒潜伏期进行明确的研究。当接受辐射或白消安调节、免疫缺陷的 NSG 小鼠被移植人类造血干细胞时，来自骨髓的人类细胞进入大脑并分化以表达小胶质细胞特异性标记物。感染具有复制能力的艾滋病毒后，在这些骨髓来源的人类小胶质细胞中检测到了病毒。通过开发能够选择性逆转小胶质细胞中 HIV 潜伏期的化合物，将大大加强对该模型中 HIV 潜伏期的研究。我们的研究已确定 CoREST 抑制复合体的成员是大鼠和人类小胶质细胞系中小胶质细胞中 HIV 潜伏期的关键调节因子。单胺氧化酶 (MAO) 和潜在的 CoREST 抑制剂苯乙肼具有脑渗透性，能够刺激人类小胶质细胞系和从感染 HIV 的人源化小鼠大脑中回收的人类胶质细胞产生 HIV。因此，我们开发的人源化小鼠作为模型系统显示出巨大的前景，可用于开发旨在定义和减少中枢神经系统储存库的策略。
Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir.
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DOI：
10.1073/pnas.1205858109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Capotondo, Alessia;Milazzo, Rita;Biffi, Alessandra
通讯作者：
Biffi, Alessandra
DOI：
10.1523/jneurosci.5473-10.2011
发表时间：
2011-03-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dash PK;Gorantla S;Gendelman HE;Knibbe J;Casale GP;Makarov E;Epstein AA;Gelbard HA;Boska MD;Poluektova LY
通讯作者：
Poluektova LY
影响因子：
15.1
作者：
Boska MD;Dash PK;Knibbe J;Epstein AA;Akhter SP;Fields N;High R;Makarov E;Bonasera S;Gelbard HA;Poluektova LY;Gendelman HE;Gorantla S
通讯作者：
Gorantla S
影响因子：
6.4
作者：
Dahl, Viktor;Gisslen, Magnus;Palmer, Sarah
通讯作者：
Palmer, Sarah
影响因子：
11.2
作者：
EPSTEIN, LG;GENDELMAN, HE
通讯作者：
GENDELMAN, HE