CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice.
CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice.
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DOI：
10.1038/s41598-023-33491-7
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发表时间：
2023-04-21
影响因子：
4.6
通讯作者：
Volsky, David J.
中科院分区：
文献类型：
--
作者：
Kim, Boe-Hyun;Hadas, Eran;Kelschenbach, Jennifer;Chao, Wei;Gu, Chao-Jiang;Potash, Mary Jane;Volsky, David J.
HIV在感染后几天内进入大脑，导致多达一半的感染者神经认知障碍（NCI），尽管有抑制性抗逆转录病毒治疗。据信，该病毒通过对主要单核细胞趋化因子CCL2的趋化性进入受感染单核细胞中的脑，但CCL2在已建立的NCI中的作用尚未完全确定。我们在用EcoHIV感染常规和CCL2基因敲除小鼠期间解决了这个问题，其中NCI可以在行为测试中得到验证。EcoHIV在感染后5天内进入小鼠大脑，但NCI在感染后25天开始逐渐发展为已建立的认知疾病。通过腹腔注射病毒感染的CCL2基因敲除小鼠未发生脑感染和NCI。然而，当EcoHIV直接注射到大脑中时，CCL2敲除小鼠发展为NCI。CCL2或其主要受体CCR2的敲除略微降低了培养物中的巨噬细胞感染。在EcoHIV感染之前和期间用CCL2转录抑制剂bindarit治疗小鼠，可预防脑感染和NCI，并减少巨噬细胞感染。相比之下，在感染后4周对小鼠进行的bindarit治疗既不影响脑病毒负荷也不影响NCI。基于这些发现，我们认为HIV主要通过受感染的单核细胞进入大脑，但驻留的脑细胞足以维持NCI。这些发现表明，NCI治疗必须在大脑内起作用。
HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but the roles of CCL2 in established NCI are not fully defined. We addressed this question during infection of conventional and CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. EcoHIV enters mouse brain within 5 days of infection, but NCI develops gradually with established cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI and reduced macrophage infection. In contrast, bindarit treatment of mice 4 weeks after infection affected neither brain virus burden nor NCI. Based on these findings we propose that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. These findings suggest that NCI therapy must act within the brain.
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影响因子：
16.1
作者：
Goodkin, Karl;Miller, Eric N.;Sacktor, Ned C.
通讯作者：
Sacktor, Ned C.
DOI：
10.1097/nen.0000000000000026
发表时间：
2014-01-01
影响因子：
3.2
作者：
He, Hongxia;Sharer, Leroy R.;Volsky, David J.
通讯作者：
Volsky, David J.
影响因子：
7.6
作者：
Falcon, Edgardo;Browne, Caroline A.;Lucki, Irwin
通讯作者：
Lucki, Irwin
影响因子：
3.3
作者：
Bell, MD;Taub, DD;Perry, VH
通讯作者：
Perry, VH
DOI：
10.1073/pnas.82.20.7086
发表时间：
1985-01-01
影响因子：
11.1
作者：
GENDELMAN, HE;NARAYAN, O;GHOTBI, Z
通讯作者：
GHOTBI, Z