Fitting Sylvia, McLaurin Kristen A, Booze Rosemarie M, Mactutus Charles F
University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA.
Int J Dev Neurosci. 2018 Apr;65:66-82. doi: 10.1016/j.ijdevneu.2017.10.009. Epub 2017 Oct 27.
Despite the availability of antiretroviral prophylactic treatment, pediatric human immunodeficiency virus type 1 (HIV-1) continues to be a significant risk factor in the post-cART era. The time of infection (i.e., during pregnancy, delivery or breastfeeding) may play a role in the development of neurocognitive deficits in pediatric HIV-1. HIV-1 viral protein exposure on postnatal day (P)1, preceding the postnatal brain growth spurt in rats, had deleterious effects on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2008a,b). In the present study, rats were stereotaxically injected with HIV-1 viral proteins, including Tat and gp120, on P10 to further examine the role of timing on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2010). The dose-dependent virotoxin effects observed across development following P10 Tat exposure were specific to spatial learning and absent from prepulse inhibition and locomotor activity. A relationship between alterations in spatial learning and/or memory and hippocampal anatomical parameters was noted. Specifically, the estimated number of neurons and astrocytes in the hilus of the dentate gyrus explained 70% of the variance of search behavior in Morris water maze acquisition training for adolescents and 65% of the variance for adults; a brain-behavior relationship consistent with observations following P1 viral protein exposure. Collectively, late viral protein exposure (P10) results in selective alterations in neurocognitive development without modifying measures of somatic growth, preattentive processing, or locomotor activity, as characterized by early viral protein exposure (P1). Thus, timing may be a critical factor in disease progression, with children infected with HIV earlier in life being more vulnerable to CNS disease.
尽管有抗逆转录病毒预防性治疗，但在抗逆转录病毒治疗（cART）时代之后，儿童1型人类免疫缺陷病毒（HIV-1）仍然是一个重要的风险因素。感染时间（即在妊娠、分娩或母乳喂养期间）可能在儿童HIV-1神经认知缺陷的发展中起作用。在大鼠出生后大脑生长突增之前的出生后第（P）1天暴露于HIV-1病毒蛋白，对神经认知发育和海马体的解剖学参数有有害影响（菲廷等人，2008a、b）。在本研究中，在出生后第10天对大鼠进行立体定向注射HIV-1病毒蛋白，包括Tat和gp120，以进一步研究时间对神经认知发育和海马体解剖学参数的作用（菲廷等人，2010）。在出生后第10天暴露于Tat后，在整个发育过程中观察到的剂量依赖性病毒毒素效应特定于空间学习，而在预脉冲抑制和运动活动中不存在。注意到空间学习和/或记忆改变与海马体解剖学参数之间的关系。具体而言，齿状回门区神经元和星形胶质细胞的估计数量解释了青少年在莫里斯水迷宫获取训练中搜索行为方差的70%，以及成年人方差的65%；这种脑-行为关系与出生后第1天暴露于病毒蛋白后的观察结果一致。总的来说，晚期病毒蛋白暴露（出生后第10天）导致神经认知发育的选择性改变，而不改变躯体生长、注意力前加工或运动活动的指标，早期病毒蛋白暴露（出生后第1天）的特征即在于此。因此，时间可能是疾病进展的关键因素，生命早期感染HIV的儿童更容易患中枢神经系统疾病。
