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.

尽管接受了抑制性抗逆转录病毒治疗，艾滋病毒在感染后几天内就会进入大脑，导致多达一半的感染者出现神经认知障碍（NCI）。据信，该病毒通过对主要单核细胞趋化因子 CCL2 的趋化作用进入受感染单核细胞的大脑，但 CCL2 在已建立的 NCI 中的作用尚未完全确定。我们在感染 EcoHIV 的传统小鼠和 CCL2 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 逐渐发展，并在感染后 25 天开始形成认知疾病。腹腔注射病毒感染的CCL2基因敲除小鼠未出现脑部感染和NCI。然而，当EcoHIV直接注射到大脑中时，CCL2基因敲除小鼠出现了NCI。敲除 CCL2 或其主要受体 CCR2，可略微减少培养物中巨噬细胞的感染。在 EcoHIV 感染之前和感染期间，用 CCL2 转录抑制剂 bindarit 治疗小鼠，可预防脑部感染和 NCI，并减少巨噬细胞感染。相比之下，感染 4 周后对小鼠进行 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，但常驻脑细胞足以维持 NCI。这些发现表明 NCI 疗法必须在大脑内起作用。