Single genome analysis reveals genetic characteristics of Neuroadaptation across HIV-1 envelope.
Single genome analysis reveals genetic characteristics of Neuroadaptation across HIV-1 envelope.
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DOI：
10.1186/s12977-014-0065-0
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发表时间：
2014-08-15
期刊：
影响因子：
3.3
通讯作者：
Markowitz M
中科院分区：
文献类型：
--
作者：
Evering TH;Kamau E;St Bernard L;Farmer CB;Kong XP;Markowitz M
高效的联合抗逆转录病毒疗法（cART）的广泛使用已导致艾滋病毒相关性痴呆（HAD）的发病率显著降低。尽管取得了这些进展，但HIV-1相关神经认知障碍（HANDs）的患病率估计约为40%-50%。在cART时代，这种疾病负担的大部分是无症状神经认知障碍和轻度神经认知障碍（分别为ANI和MND）。虽然没有HAD严重，但这些诊断带来了相当大的发病率。在这项横断面研究中，使用单基因组扩增（SGA）对717个全长HIV-1包膜（env）进化枝B变异体进行测序，这些变异体来自15个神经认知功能（NCN）正常、ANI和MND的慢性感染HIV阳性个体的配对脑脊液（CSF）和血浆样本。不同疾病状态和cART使用史存在不同程度的区室化。在具有区室化病毒的个体中，CSF中的平均HIV-1 env群体多样性低于血浆衍生变体。总体而言，平均V1 V2环长度较短的CSF衍生的准种相比，同期的血浆人群，这被发现与较低的平均数N-连接的糖基化位点在该地区。在gp 120的可变区和恒定区以及gp 41中鉴定了许多与CSF中的区室化强烈相关的离散氨基酸位置。相关突变分析进一步确定，这些区室化“热点”位置中的氨基酸残基子集彼此强烈相关，表明它们可能在病毒变体适应CSF中发挥重要的可定义的作用。在HIV-1 gp 120的晶体结构得到充分支持的背景下，对这些热点的分析表明，在所识别的残基处的氨基酸差异可能有助于CSF中的病毒区室化的机制。对来自cART时代神经认知功能正常和最常见HAND诊断受试者的SGA衍生全长HIV-1 env的详细分析，使我们能够鉴定新的并确认先前描述的神经适应性HIV-1 env遗传决定因素，并将潜在的基序与HIV-1 env结构和功能联系起来。本文的在线版本（doi：10.1186/s12977-014-0065-0）包含补充材料，可供授权用户使用。
The widespread use of highly effective, combination antiretroviral therapy (cART) has led to a significant reduction in the incidence of HIV-associated dementia (HAD). Despite these advances, the prevalence of HIV-1 associated neurocognitive disorders (HANDs) has been estimated at approximately 40%-50%. In the cART era, the majority of this disease burden is represented by asymptomatic neurocognitive impairment and mild neurocognitive disorder (ANI and MND respectively). Although less severe than HAD, these diagnoses carry with them substantial morbidity. In this cross-sectional study, single genome amplification (SGA) was used to sequence 717 full-length HIV-1 envelope (env) clade B variants from the paired cerebrospinal fluid (CSF) and blood plasma samples of fifteen chronically infected HIV-positive individuals with normal neurocognitive performance (NCN), ANI and MND. Various degrees of compartmentalization were found across disease states and history of cART utilization. In individuals with compartmentalized virus, mean HIV-1 env population diversity was lower in the CSF than plasma-derived variants. Overall, mean V1V2 loop length was shorter in CSF-derived quasispecies when compared to contemporaneous plasma populations, and this was found to correlate with a lower mean number of N-linked glycosylation sites in this region. A number of discrete amino acid positions that correlate strongly with compartmentalization in the CSF were identified in both variable and constant regions of gp120 as well as in gp41. Correlated mutation analyses further identified that a subset of amino acid residues in these compartmentalization “hot spot” positions were strongly correlated with one another, suggesting they may play an important, definable role in the adaptation of viral variants to the CSF. Analysis of these hot spots in the context of a well-supported crystal structure of HIV-1 gp120 suggests mechanisms through which amino acid differences at the identified residues might contribute to viral compartmentalization in the CSF. The detailed analyses of SGA-derived full length HIV-1 env from subjects with both normal neurocognitive performance and the most common HAND diagnoses in the cART era allow us to identify novel and confirm previously described HIV-1 env genetic determinants of neuroadaptation and relate potential motifs to HIV-1 env structure and function. The online version of this article (doi:10.1186/s12977-014-0065-0) contains supplementary material, which is available to authorized users.
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