Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada.
Montreal Clinical Research Institute, Montréal, Canada.
Retrovirology. 2017 Oct 16;14(1):47. doi: 10.1186/s12977-017-0370-5.
In patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question. HIV-1 infects and replicates in resident microglia and trafficking macrophages within the brain although the impact of individual ART drugs on viral infection within these brain myeloid cells is unknown. Herein, the effects of contemporary ART drugs were investigated using in vitro and in vivo models of HIV-1 brain infection.
The EC values for specific ART drugs in HIV-infected human microglia were significantly higher compared to bone marrow-derived macrophages and peripheral blood mononuclear cells. Intracellular ART drug concentrations in microglia were significantly lower than in human lymphocytes. In vivo brain concentrations of ART drugs in mice were 10 to 100-fold less in brain tissues compared with plasma and liver levels. In brain tissues from untreated HIV-infected BLT mice, HIV-encoded RNA, DNA and p24 were present in human leukocytes while ART eradicated viral RNA and DNA in both brain and plasma. Interruption of ART resulted in detectable viral RNA and DNA and increased human CD68 expression in brains of HIV-infected BLT mice. In aviremic HIV/AIDS patients receiving effective ART, brain tissues that were collected within hours of last ART dosing showed HIV-encoded RNA and DNA with associated neuroinflammatory responses.
ART drugs show variable concentrations and efficacies in brain myeloid cells and tissues in drug-specific manner. Despite low drug concentrations in brain, experimental ART suppressed HIV-1 infection in brain although HIV/AIDS patients receiving effective ART had detectable HIV-1 in brain. These findings suggest that viral suppression in brain is feasible but new approaches to enhancing ART efficacy and concentrations in brain are required for sustained HIV-1 eradication from brain.
在接受抗逆转录病毒疗法 (ART) 的 HIV/AIDS 患者中，HIV-1 在脑组织中的持续存在是一个重要且未得到解答的问题。HIV-1 感染并在大脑中的常驻小胶质细胞和迁移巨噬细胞中复制，尽管个别 ART 药物对这些脑髓细胞中的病毒感染的影响尚不清楚。在此，使用 HIV-1 脑感染的体外和体内模型研究了当代 ART 药物的作用。
与骨髓来源的巨噬细胞和外周血单核细胞相比，感染 HIV 的人小胶质细胞中特定 ART 药物的 EC 值明显更高。小胶质细胞中的细胞内 ART 药物浓度明显低于人淋巴细胞。在接受 ART 治疗的 HIV 感染 BLT 小鼠的脑组织中，ART 药物的浓度比血浆和肝脏水平低 10 到 100 倍。在未经治疗的 HIV 感染 BLT 小鼠的脑组织中，HIV 编码的 RNA、DNA 和 p24 存在于人白细胞中，而 ART 消除了大脑和血浆中的病毒 RNA 和 DNA。中断 ART 导致在 HIV 感染 BLT 小鼠的大脑中可检测到病毒 RNA 和 DNA 以及人类 CD68 表达增加。在接受有效 ART 的无病毒血症 HIV/AIDS 患者中，在最后一次 ART 给药后数小时内采集的脑组织显示 HIV 编码的 RNA 和 DNA 以及相关的神经炎症反应。
ART 药物以药物特异性的方式在脑髓细胞和组织中表现出不同的浓度和疗效。尽管大脑中的药物浓度较低，但实验性 ART 抑制了 HIV-1 感染，尽管接受有效 ART 的 HIV/AIDS 患者的大脑中可检测到 HIV-1。这些发现表明，大脑中的病毒抑制是可行的，但需要新的方法来提高 ART 的疗效和大脑中的浓度，以从大脑中持续清除 HIV-1。
