HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and β-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.

中文翻译：

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HIV相关神经认知障碍中间组织病理学表型的候选基因研究。

HIV 相关神经认知障碍 (HAND) 描述了由 HIV-1 感染引起的一系列神经心理障碍。虽然导致 HAND 的细胞和生理事件的顺序仍然不清楚，但它可能涉及慢性神经炎症。已经报道了增加 HAND 风险的宿主遗传标记，但缺乏此类研究的重复性，可能是由于跨研究的行为表型应用不一致。在当前的研究中，我们使用组织病理学表型来验证 HAND 的假定风险等位基因。国家 NeuroAIDS Tissue Consortium，一项对 HIV 神经系统表现的纵向研究。数据和标本来自 175 名感染 HIV 的成年人。在确定神经认知功能的几个潜在协变量后，我们量化了额叶中与神经认知功能相关的六种组织病理学标志物的水平：SYP、MAP 2、HLA-DR、Iba1、GFAP 和 β-淀粉样蛋白。然后，我们确定了 15 个候选基因的等位基因与神经认知功能和组织病理学标记的关联。最后，我们使用基于多阶段线性回归的中介分析方法，根据我们的数据确定了最合理的因果途径。没有一个遗传标记与神经认知功能相关。在组织病理学标志物中，只有 MAP 2 和 SYP 与神经认知功能相关；然而，MAP 2 和 SYP 不随基因型而变化。中介分析表明突触前变性 (SYP) 导致体细胞树突变性 (MAP 2) 并最终导致神经认知障碍的因果途径。该研究不支持宿主基因型在 HAND 基础组织病理学中的作用。这些发现进一步支持突触树突变性作为 HAND 的近端潜在神经病理学底物。