Differential effects on the survival of neuronal and non-neuronal cells after infection by herpes simplex virus type 1 mutants
Differential effects on the survival of neuronal and non-neuronal cells after infection by herpes simplex virus type 1 mutants
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DOI：
10.3109/13550289909015814
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发表时间：
1999-06-01
影响因子：
3.2
通讯作者：
Schimmang, T
中科院分区：
文献类型：
--
作者：
Garrido, JJ;Carnicero, E;Schimmang, T
单纯疱疹病毒1型(HSV-1)的复制缺陷突变体是将基因转移到有丝分裂后神经元的强大工具，并有望成为体内基因治疗方案。为了评价这些载体治疗贫血症的有效性和安全性，我们用即刻早期基因IE2(5dl1.2)或IE3(D120)缺陷的HSV突变株感染分离的耳蜗神经节。我们的结果显示，这些突变体导致的神经细胞和非神经细胞的存活存在显著差异。令人惊讶的是，不同浓度的5dl1.2感染后的耳蜗神经元在培养2天后存活率显著增加。相反，许多非神经细胞经历了凋亡，使细胞数量减少到不到50%。在神经细胞和非神经细胞类型中，我们也观察到形态上有重要变化的一群细胞。对感染D120的分离耳蜗神经节的分析表明，神经元存活率降低，而非神经细胞几乎没有受到影响。为了进一步表征和比较5DL1.2和D120的作用，我们对中枢神经系统衍生的细胞类型进行了转导，包括皮质神经元和星形胶质细胞。同样，在耳蜗神经元中观察到，感染5dl1.2导致皮质神经元存活率增加，而d120表现出细胞毒性效应。两种HSV缺失突变体都同样降低了星形胶质细胞的存活率。我们得出结论，早期基因缺陷的HSV-1突变株根据细胞环境的不同而导致非常不同的细胞病变表型。这些差异的可能原因，如细胞和病毒基因表达的不同模式，以及使用HSV-1载体进行基因转移的意义进行了讨论。
Replication-defective mutants of herpes simplex virus type 1 (HSV-1) are powerful tools to transfer genes into postmitotic neurons and show promise for gene therapy protocols in vivo. To evaluate the efficacy and safety of these vectors for the treatment of dearness we infected dissociated cochlear ganglia with HSV mutants defective in the immediate early genes IE 2 (5dl1.2) or IE 3 (d120). Our results reveal striking differences in the survival of neuronal and non-neuronal cells caused by these mutants. Surprisingly, cochlear neurons infected with 5dl1.2 at various concentrations show a significant increase in survival after 2 days in culture. In contrast, many non-neuronal cells undergo apoptosis reducing cell number to less than 50%. In both neuronal and nonneuronal cell types we also observe a population of cells with important changes in morphology. Analysis of dissociated cochlear ganglia infected with d120 reveals a decrease of neuronal survival, whereas non-neuronal cells were almost unaffected. To further characterize and compare the effects of 5dl1.2 and d120 we transduced central nervous system-derived cell types including cortical neurons and astrocytes. Similarly, as observed for cochlear neurons, infection with 5dl1.2 results in increased survival of cortical neurons, whereas d120 shows cytotoxic effects. Survival of astrocytes is equally reduced by both HSV deletion mutants. We conclude that HSV-1 mutants defective in immediate early genes cause very distinct cytopathic phenotypes depending on the cellular context. Possible reasons for these differences, like various patterns of cellular and viral gene expression, and the implications for the use of HSV-1 vectors for gene transfer are discussed.