Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain.
Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain.
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DOI：
10.1097/qad.0000000000000074
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发表时间：
2013-11-28
期刊：
影响因子：
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通讯作者：
Mankowski JL
中科院分区：
文献类型：
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作者：
Kelly KM;Beck SE;Metcalf Pate KA;Queen SE;Dorsey JL;Adams RJ;Avery LB;Hubbard W;Tarwater PM;Mankowski JL
尽管采用了抑制性联合抗逆转录病毒治疗，但艾滋病毒相关的神经认知缺陷仍然是一个挑战。鉴于HIV诱导的中枢神经系统（CNS）疾病与免疫活化巨噬细胞中HIV复制之间的关联，CCR 5拮抗剂可通过调节炎症信号传导和限制病毒复制来减轻CNS疾病。为了确定在早期感染期间启动CCR 5抑制是否会改变中枢神经系统疾病的进展，比较了接受马拉韦罗（MVC）治疗的猿猴免疫缺陷病毒（SIV）感染的猕猴与未经治疗的SIV感染的猕猴之间的结果。6只SIV感染的恒河猴从接种后24天开始接受MVC单药治疗5个月; 22只SIV感染的动物作为未治疗的对照。通过qRT-PCR测量血浆、脑脊液和脑中的SIV RNA水平以及TNFα和CCL 2的CNS表达。通过图像分析测量脑中CD 68和淀粉样前体蛋白的免疫染色。ELISA法测定血浆sCD 163水平。脑中SIV RNA和前病毒DNA水平在MVC治疗中显著降低，表明CCR 5抑制减少了SIV的CNS复制，并可能减少CNS潜伏病毒库。MVC处理还降低了单核细胞和巨噬细胞的活化，表现为CNS CD 68免疫染色和血浆sCD 163水平，并降低了脑中TNFα和CCL 2 RNA的表达。治疗还减少了轴突淀粉样前体蛋白免疫染色的水平，目前在未感染的动物，与神经保护。CCR 5抑制剂可以通过减少炎症和限制病毒在大脑中的复制来预防HIV感染者的神经系统疾病。此外，CCR 5抑制剂可减少CNS中的潜伏病毒储库。在联合抗逆转录病毒治疗方案中加入CCR 5抑制剂可能会提供多种神经保护益处。
HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV-induced central nervous system (CNS) disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication. To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between simian immunodeficiency virus (SIV)-infected macaques treated with maraviroc (MVC) versus untreated SIV-infected macaques. Six SIV-infected rhesus macaques were treated with MVC monotherapy for 5 months beginning 24 days postinoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, cerobrospinal fluid, and brain, and CNS expression of TNFα and CCL2 were measured by qRT-PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA. SIV RNA and proviral DNA levels in brain were markedly lower with MVC treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. MVC treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFα and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection. CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined antiretroviral regimens may offer multiple neuroprotective benefits.