Epstein L G, Gelbard H A
Department of Neurology, University of Rochester, New York, USA.
J Leukoc Biol. 1999 Apr;65(4):453-7. doi: 10.1002/jlb.65.4.453.
HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. In infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor alpha (TNF-alpha) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood-brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1-infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide "neuroprotection" from excitotoxic neuronal injury.
HIV-1感染神经系统会导致神经元损伤和死亡，从而在成人和儿童中引发认知、运动及行为功能障碍。在婴儿中，HIV-1感染的一个特征是脑生长受损，导致继发性小头畸形，发病于2至4个月龄之间。由于这个年龄段活跃的突触发生和修剪过程伴随着兴奋性氨基酸（EAA）受体的过度表达，这个产后脑发育阶段特别容易受到兴奋性毒性神经元损伤。HIV-1感染脑小胶质细胞和血管周围巨噬细胞会导致慢性炎症，病理表现为弥漫性小胶质细胞活化和反应性星形胶质细胞增生。活化小胶质细胞的几种炎症产物，包括肿瘤坏死因子α（TNF-α）和血小板活化因子（PAF），已被证明可作为神经元毒素。这种毒性作用可通过阻断NMDA（或AMPA）谷氨酸受体来拮抗，这表明（轻度）兴奋性毒性会导致氧化应激、神经元损伤和细胞凋亡。HIV-1感染和慢性炎症也可能导致血脑屏障破坏，并可能导致有毒病毒或细胞产物或更多HIV-1感染细胞进一步进入中枢神经系统。我们假设，HIV-1感染期间小胶质细胞的长期活化是受影响婴儿神经元损伤和脑生长受损的基础。进一步研究HIV-1感染/活化的小胶质细胞与发育中神经元之间的相互作用似乎很有必要。目前对HIV神经发病机制的理解意味着治疗策略应针对小胶质细胞中持续的免疫激活，尝试修复血脑屏障的完整性，并提供针对兴奋性毒性神经元损伤的“神经保护”。
