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Human immunodeficiency virus and host cell lipids. Interesting pathways in research for a new HIV therapy.
Progress in Lipid Research ( IF 13.6 ) Pub Date : 2001-11-06 , DOI: 10.1016/s0163-7827(01)00019-4
Jeanine Raulin 1
Affiliation  

It has been reported in the literature that biological membranes arising from HIV-induced cell fusion, as well as syncytium formation between infected and non-infected cells and those involved in transduction, viral DNA nuclear import and virion budding from the host cell, are all made of proteins, a phospholipid (P) bilayer and cholesterol (C). However, the P/C molar ratio is higher in the retroviral envelope than in the plasma membrane where they originate, and higher than in the nuclear envelope. Mechanisms are described which elucidate this puzzling fact, as well as cholesterol-dependent leakage and pore formation during cell fusion. Fatty acylation of viral and host cell proteins is required to direct them to membranes. Detergent-insoluble microdomains enriched in cholesterol and sphingolipids, termed either DIGs (detergent-insoluble glycolipid-enriched complexes), DRMs (detergent resistant membranes), TIFFs (Triton-insoluble floating fractions) or GEMs (glycolipid-enriched membranes), function as platforms for attachment of proteins in the process of signal transduction. HIV-SUgp120 (HIV-surface glycoprotein), T-cell receptor (TCR)-CD4+ and co-receptors promote aggregation of these lipid "rafts" which concentrate the Src family tyrosine kinases SFKs (PTK, Lyn, Fyn, Lck), GPI (glycosyl phosphatidylinositol)-anchored proteins, and phosphatidylinositol kinases PI(3)K and PI(4)K, inducing cell signalling. HIV-SUgp120 transduces the activation signal and provokes the formation of polyunsaturated fatty acid (PUFA) metabolites, i.e. the prostaglandin PGE2 suppressor of immune function and inhibitor of cytotoxic T-lymphocyte (CTL) proliferation, while PGB2 activates SFKs and increases mRNA expression, as well as NFkappaB (nuclear transcription factor) translocation to nucleus. HIV nuclear import, DNA integration, chromatin template capacity may be mediated by the lipid environment. The lipid-enriched microdomains from which HIV-1 buds, may explain the high level of cholesterol and sphingolipids in the viral envelope, since host cell rafts become a viral coat. HIV-1 infection induces alteration of cellular lipids: (1) shift in phospholipid synthesis to neutral lipids associated with the viral load, polyunsaturated fatty acid (PUFA) peroxidation, and n-3 deficiency with deregulation of cytokines and PPAR-gamma (peroxisome proliferator-activated receptor-gamma), and (2) alloimmune phospholipid antibody production in which antibodies to cardiolipin and to phosphatidylserine are most prevalent, due to the destruction of mitochondrial membranes and progression of lymphocyte apoptosis. The current highly active anti-retroviral therapy, including both viral reverse transcriptase (RT) inhibitors (NRTIs and NNRTIs, nucleoside and non-nucleoside RT inhibitors) and protease inhibitors (PIs), induces side-effects in the long term. Lipodystrophy (LD), consists of peripheral lipoatrophy associated with central fat accumulation (called "crixbelly" and "buffalo hump"), insulin resistance, elevation of very low density lipoproteins, decrease in high density lipoproteins and inhibition of adipocyte differentiation. LD syndrome appears to be induced by PIs that inhibit GLUT4, glucose transporter isoform, and by NRTIs which provoke mitochondrial failure. New therapeutic strategies assessed: (1) inhibition of the viral integrase and/or HIV entry into cells through natural products or their derivatives, (2) inhibition of HIV-1 entry into macrophages pretreated with Gram-negative bacterial lipopolysaccharide, (3) vaccination with multi-lipopeptides, i.e. sequences of HIV-1 peptides with CD4+ T-cell and B-cell epitopes, modified by adding a lipid tail to one end, which produce HIV-specific CTL and multispecific immune responses in most of the vaccinated subjects and (4) stimulation of antiviral drug activity with lipid-prodrugs targeting viral RT, polymerase, integrase, or aspartyl-protease.

中文翻译:

人免疫缺陷病毒和宿主细胞脂质。新型HIV治疗研究的有趣途径。

据文献报道,由HIV诱导的细胞融合产生的生物膜,以及感染和未感染细胞之间的合胞体形成以及涉及转导,病毒DNA核输入和从宿主细胞出芽的病毒体的所有细胞都形成了合胞体。由蛋白质,磷脂(P)双层和胆固醇(C)制成。但是,逆转录病毒包膜中的P / C摩尔比高于其起源的质膜中的P / C摩尔比,也高于核包膜中的P / C摩尔比。描述了阐明这一令人困惑的事实以及在细胞融合过程中胆固醇依赖性渗漏和孔形成的机制。需要将病毒和宿主细胞蛋白进行脂肪酰化才能将其引导到膜上。富含胆固醇和鞘脂的不溶于洗涤剂的微区,称为DIG(不溶于洗涤剂的富含糖脂的复合物),DRM(耐洗涤剂的膜),TIFF(不溶于Triton的漂浮级分)或GEM(富含糖脂的膜)在信号转导过程中充当蛋白质附着的平台。HIV-SUgp120(HIV表面糖蛋白),T细胞受体(TCR)-CD4 +和共受体促进这些脂质“筏”的聚集,从而使Src家族酪氨酸激酶SFK(PTK,Lyn,Fyn,Lck),GPI集中(糖基磷脂酰肌醇)锚定的蛋白,以及磷脂酰肌醇激酶PI(3)K和PI(4)K,诱导细胞信号传导。HIV-SUgp120转导激活信号并激发多不饱和脂肪酸(PUFA)代谢产物的形成,即 前列腺素PGE2的免疫功能抑制剂和细胞毒性T淋巴细胞(CTL)增殖的抑制剂,而PGB2激活SFKs和增加mRNA表达,以及NFkappaB(核转录因子)易位至细胞核。HIV的核输入,DNA整合,染色质模板能力可能由脂质环境介导。HIV-1发芽的富含脂质的微区可能解释了病毒包膜中高水平的胆固醇和鞘脂,因为宿主细胞筏变成了病毒外壳。HIV-1感染引起细胞脂质改变:(1)磷脂合成转变为与病毒载量,多不饱和脂肪酸(PUFA)过氧化和n-3缺乏相关的中性脂质,其中细胞因子和PPAR-γ(过氧化物酶体增殖物)失控激活的受体-γ),(2)同种免疫磷脂抗体的产生,其中由于线粒体膜的破坏和淋巴细胞凋亡的进展,针对心磷脂和磷脂酰丝氨酸的抗体最为普遍。目前,包括病毒逆转录酶(RT)抑制剂(NRTI和NNRTIs,核苷和非核苷RT抑制剂)和蛋白酶抑制剂(PIs)在内的高活性抗逆转录病毒疗法会长期产生副作用。脂肪营养不良(LD)由与中央脂肪堆积(称为“ cribbelly”和“ buffalo hump”)相关的周围脂肪萎缩,胰岛素抵抗,极低密度脂蛋白升高,高密度脂蛋白降低和脂肪细胞分化抑制组成。LD综合征似乎是由抑制GLUT4的PI诱导的,葡萄糖转运蛋白亚型,并由NRTIs引起线粒体衰竭。评估了新的治疗策略:(1)抑制病毒整合酶和/或HIV通过天然产物或其衍生物进入细胞;(2)抑制HIV-1进入用革兰氏阴性细菌脂多糖预处理的巨噬细胞;(3)疫苗接种带有多脂肽,即带有CD4 + T细胞和B细胞表位的HIV-1肽序列,通过在一端添加脂质尾部进行修饰,从而在大多数接种疫苗的受试者中产生HIV特异性CTL和多特异性免疫反应,并且(4)用靶向病毒RT,聚合酶,整合酶或天冬氨酰蛋白酶的脂质前药刺激抗病毒药物活性。
更新日期:2019-11-01
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