Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer’s Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies. NOD/scid–IL-2Rγcnull mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal’s blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA. HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor–related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist. Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies.

中文翻译：

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CCR5 拮抗剂可减少 HIV 感染的 hu-PBL-NSG 小鼠中 HIV 诱导的淀粉样变、tau 病理、神经变性和血脑屏障改变


50% 的 HIV 感染者存在神经认知障碍，并且通常与阿尔茨海默病 (AD) 样脑部病变相关，包括β-淀粉样蛋白 (Aβ) 和 Tau 过度磷酸化增加。在这里，我们的目的是确定 HIV-1 感染是否会在 HIV/AIDS 人源化小鼠模型中引起 AD 样病理，以及 CCR5 拮抗剂马拉韦罗是否会改变 HIV 诱导的病理。植入人血白细胞的 NOD/scid–IL-2Rγcnull 小鼠感染 HIV-1，不进行治疗或用马拉韦罗（120 mg/kg，每天两次）治疗。每周通过流式细胞术对动物血液中的人类细胞进行定量。感染后第3周处死动物；使用 p24 抗原 ELISA、RNAscope 和 qPCR 对血液和组织病毒载量进行定量。人类 (HLA-DR+) 细胞、Aβ-42、磷酸 Tau、神经元标记物（MAP 2、NeuN、神经丝-L）、γ-分泌酶激活蛋白 (GSAP) 和血脑屏障 (BBB) 紧密连接 (TJ)通过免疫组织化学、免疫荧光、免疫印迹和 qPCR 对脑组织中的蛋白质表达和转录进行定量。通过 ELISA 对血浆 Aβ-42、Aβ-42 细胞摄取、释放和跨内皮转运进行定量。 HIV-1 显着降低人类 (h)CD4+ T 细胞和 hCD4/hCD8 比率；降低BBB TJ蛋白claudin-5、ZO-1、ZO-2的表达；脑组织中的 HLA-DR+ 细胞增加。值得注意的是，感染 HIV 的动物表现出血浆和大脑 Aβ-42 和磷酸 Tau（苏氨酸 181、苏氨酸 231、丝氨酸 396、丝氨酸 199）增加，这与 GSAP（一种催化 Aβ 形成的酶）转录上调以及 MAP 2、NeuN、和神经丝-L。 Maraviroc 治疗显着降低血液和脑部病毒载量，防止 HIV 引起的神经元标志物和 TJ 蛋白丢失；减少 HLA-DR+ 细胞在脑组织中的浸润，显着减少 HIV 诱导的 Aβ-42、GSAP 和磷酸 Tau 的增加。 Maraviroc 还减少了人巨噬细胞中 Aβ 的保留并增加了 Aβ 的释放。降低人脑内皮细胞中晚期糖基化终末产物 (RAGE) 受体并增加低密度脂蛋白受体相关蛋白 1 (LRP1) 表达。 Maraviroc 诱导 Aβ 跨内皮转运，可被 LRP1 拮抗剂阻断，但不能被 RAGE 拮抗剂阻断。 Maraviroc 显着减少 HIV 诱导的淀粉样蛋白生成、GSAP、磷酸化 Tau、神经变性、BBB 改变和中枢神经系统白细胞浸润。 Maraviroc 通过 LRP1 途径增加细胞 Aβ 流出和跨内皮 Aβ 转运。因此，针对 CCR5 的治疗可以减少病毒血症，保护 BBB 和神经元，增加大脑 Aβ 流出，并减少 AD 样神经病理学。