Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence.
Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence.
复制标题
DOI：
10.1186/1742-4690-8-44
复制
发表时间：
2011-06-06
期刊：
影响因子：
3.3
通讯作者：
Power C
中科院分区：
文献类型：
--
作者：
Na H;Acharjee S;Jones G;Vivithanaporn P;Noorbakhsh F;McFarlane N;Maingat F;Ballanyi K;Pardo CA;Cohen EA;Power C
病毒的多样性和丰度决定了人类免疫缺陷病毒(HIV)-1的生物学特性和致病性。尽管抗逆转录病毒治疗的可用性越来越高，但hiv相关痴呆（HAD）仍然是HIV-1大脑感染的破坏性后果，尽管潜在的疾病机制仍不确定。本文研究了HIV-1非结构基因Vpr的分子多样性，并对来自患有或不患有HIV相关性痴呆（HAD）的HIV/AIDS患者的大脑和血液的RNA序列进行了检测，以及随后的病理生物学效应。克隆的脑源性和血源性全长vpr等位基因显示，脑源性等位基因中的氨基酸残基77将HAD （77Q）与非痴呆（ND） HIV/AIDS患者（77R）区分开来（p < 0.05），尽管vpr转录本在HAD脑中检测频率更高（p < 0.05）。编码77R-ND残基的HIV-1全长克隆在人神经胶质细胞中诱导的IFN-α、MX1和BST-2转录水平高于编码77Q-HAD的病毒（p < 0.05），但两种病毒的基因表达和复制水平相似。转染含77Q-(pVpr77Q-HAD)、77R （pVpr77R-ND）或Vpr null （pVpr(-)）载体的骨髓细胞显示pVpr77R-ND载体诱导免疫基因表达水平升高（p < 0.05），神经毒性增加（p < 0.05）。含有77Q-HAD或77R-ND基序的Vpr肽（氨基酸70-96）在暴露于人类神经元时诱导相似水平的胞质钙活化。与77Q-HAD肽相比，暴露于77R-ND肽的人胶质细胞激活了更高水平的IFN-α、MX1、PRKRA和BST-2转录物（p < 0.05）。当暴露于人类神经元时，Vpr 77R-ND肽的神经毒性也呈浓度依赖性（p < 0.05）。在小鼠基底节区立体定向植入全长Vpr、77Q-HAD或77R-ND肽后，与植入77Q-HAD肽的小鼠相比，全长Vpr和77R-ND肽引起的神经行为缺陷和神经元损伤更大（p < 0.05）。这些观察结果强调了Vpr的强大的神经致病特性，但也表明病毒多样性调节先天神经免疫和神经变性。
Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1's biology and pathogenicity. Despite the increasing availability of antiretroviral therapy, HIV-associated dementia (HAD) continues to be a devastating consequence of HIV-1 infection of the brain although the underlying disease mechanisms remain uncertain. Herein, molecular diversity within the HIV-1 non-structural gene, Vpr, was examined in RNA sequences derived from brain and blood of HIV/AIDS patients with or without HIV-associated dementia (HAD) together with the ensuing pathobiological effects. Cloned brain- and blood-derived full length vpr alleles revealed that amino acid residue 77 within the brain-derived alleles distinguished HAD (77Q) from non-demented (ND) HIV/AIDS patients (77R) (p < 0.05) although vpr transcripts were more frequently detected in HAD brains (p < 0.05). Full length HIV-1 clones encoding the 77R-ND residue induced higher IFN-α, MX1 and BST-2 transcript levels in human glia relative to the 77Q-HAD encoding virus (p < 0.05) but both viruses exhibited similar levels of gene expression and replication. Myeloid cells transfected with 77Q-(pVpr77Q-HAD), 77R (pVpr77R-ND) or Vpr null (pVpr(-))-containing vectors showed that the pVpr77R-ND vector induced higher levels of immune gene expression (p < 0.05) and increased neurotoxicity (p < 0.05). Vpr peptides (amino acids 70-96) containing the 77Q-HAD or 77R-ND motifs induced similar levels of cytosolic calcium activation when exposed to human neurons. Human glia exposed to the 77R-ND peptide activated higher transcript levels of IFN-α, MX1, PRKRA and BST-2 relative to 77Q-HAD peptide (p < 0.05). The Vpr 77R-ND peptide was also more neurotoxic in a concentration-dependent manner when exposed to human neurons (p < 0.05). Stereotaxic implantation of full length Vpr, 77Q-HAD or 77R-ND peptides into the basal ganglia of mice revealed that full length Vpr and the 77R-ND peptide caused greater neurobehavioral deficits and neuronal injury compared with 77Q-HAD peptide-implanted animals (p < 0.05). These observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.
登录
查看更多内容
HIV-1 疫苗开发中的挑战。
影响因子：
64.8
作者：
Barouch, Dan H.
通讯作者：
Barouch, Dan H.
影响因子：
6.7
作者：
Andersen JL;DeHart JL;Zimmerman ES;Ardon O;Kim B;Jacquot G;Benichou S;Planelles V
通讯作者：
Planelles V
影响因子：
11.2
作者：
Churchill, Melissa J.;Wesselingh, Steven L.;Gorry, Paul R.
通讯作者：
Gorry, Paul R.
影响因子：
5.5
作者：
Ayyavoo, V;Mahalingam, S;Weiner, DB
通讯作者：
Weiner, DB
影响因子：
3.9
作者：
Haller, Otto;Staeheli, Peter;Kochs, Georg
通讯作者：
Kochs, Georg