Johns Hopkins University School of Medicine Departments of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections, 600N, Wolfe Street, Baltimore, MS, 21287, USA.
Johns Hopkins University School of Medicine Department of Radiology and Radiological Science, 600N, Wolfe Street, Baltimore, MD, 21287, USA.
Sci Rep. 2017 Aug 10;7(1):7748. doi: 10.1038/s41598-017-07570-5.
The widespread use of combinational antiretroviral therapies (cART) in developed countries has changed the course of Human Immunodeficiency Virus (HIV) infection from an almost universally fatal disease to a chronic infection for the majority of individuals. Although cART has reduced the severity of neurological damage in HIV-infected individuals, the likelihood of cognitive impairment increases with age, and duration of infection. As cART does not suppress the expression of HIV non-structural proteins, it has been proposed that a constitutive production of HIV regulatory proteins in infected brain cells may contribute to neurological damage. However, this assumption has never been experimentally tested. Here we take advantage of the leaky tetracycline promoter system in the Tat-transgenic mouse to show that a chronic very low-level expression of Tat is associated with astrocyte activation, inflammatory cytokine expression, ceramide accumulation, reductions in brain volume, synaptic, and axonal damage that occurs over a time frame of 1 year. These data suggest that a chronic low-level production of Tat may contribute to progressive neurological damage in virally suppressed HIV-infected individuals.
在发达国家，联合抗逆转录病毒疗法（cART）的广泛应用改变了人类免疫缺陷病毒（HIV）感染的进程，使大多数人将 HIV 感染从一种几乎普遍致命的疾病转变为慢性感染。尽管 cART 降低了 HIV 感染者的神经损伤严重程度，但认知障碍的可能性会随着年龄和感染时间的增加而增加。由于 cART 不能抑制 HIV 非结构蛋白的表达，因此有人提出，感染脑细胞中 HIV 调节蛋白的持续产生可能导致神经损伤。然而，这一假设从未经过实验验证。在这里，我们利用 Tat 转基因小鼠中的漏四环素启动子系统表明，Tat 的慢性极低水平表达与星形胶质细胞激活、炎性细胞因子表达、神经酰胺积累、脑体积减少、突触和轴突损伤有关，这些变化发生在 1 年的时间内。这些数据表明，Tat 的慢性低水平产生可能导致病毒抑制的 HIV 感染者的进行性神经损伤。
