HTLV type 1 Tax transduction in microglial cells and astrocytes by lentiviral vectors.
HTLV type 1 Tax transduction in microglial cells and astrocytes by lentiviral vectors.
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HTLV 1 型通过慢病毒载体在小胶质细胞和星形胶质细胞中进行税务转导。
DOI：
10.1089/08892220050193290
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Feuer,G
中科院分区：
文献类型：
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作者：
Wrzesinski,S;Seguin,R;Liu,Y;Domville,S;Planelles,V;Massa,P;Barker,E;Antel,J;Feuer,G
人类 T 细胞白血病病毒 1 型 (HTLV-1) 感染可导致 HAM/TSP，这是一种涉及中枢神经系统神经元变性和脱髓鞘的非致命性慢性炎症性疾病。 HAM-TSP 患者脑脊液中观察到的促炎细胞因子肿瘤坏死因子 α (TNF-α)、白细胞介素 6 (IL-6) 和 IL-1 水平升高，表明 CNS 内的细胞因子失调与神经发病机制有关。据推测，HTLV-1 感染以及小胶质细胞、星形胶质细胞和巨噬细胞 TNF-α 表达增强会导致中枢神经系统中髓磷脂和少突胶质细胞的破坏。尽管 HTLV-2 感染与神经系统疾病发展之间的关联较为脆弱，但 HTLV-2 也被发现与周围神经病变相关。为了研究 HTLV Tax1 和 Tax2 在诱导这些细胞类型细胞因子失调中的作用，我们目前正在开发基于人类免疫缺陷病毒 1 型 (HIV-1) 的基因递送载体，能够在原代人类细胞中稳定共表达 HTLV-1 或 -2tax 和 eGFP 报告基因。根据 eGFP 表达评估，在人单核细胞来源的巨噬细胞和人小胶质细胞的外植培养物中可以实现高达 50% 的转导频率。初步数据表明，Tax1 表达足以上调外植的人小胶质细胞中的促炎细胞因子谱。未来的实验将比较和评估tax1和tax2基因表达对细胞促炎细胞因子表达谱的影响，并证明转导人胎儿星形胶质细胞和PBMC衍生巨噬细胞的影响。
Infection with human T cell leukemia virus type 1 (HTLV-1) can result in the development of HAM/TSP, a nonfatal, chronic inflammatory disease involving neuronal degeneration and demyelination of the central nervous system. Elevated levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1 observed in the cerebrospinal fluid of HAM-TSP patients suggest that cytokine dysregulation within the CNS is involved in neuropathogenesis. HTLV-1 infection and enhanced expression of TNF-α by microglial cells, astrocytes, and macrophages has been hypothesized to lead to the destruction of myelin and oligodendrocytes in the CNS. Although the association of HTLV-2 infection and development of neurological disease is more tenuous, HTLV-2 has also been found to be associated with peripheral neuropathies. To investigate the roles of HTLV Tax1and Tax2in the induction of cytokine disregulation in these cell types, we are currently developing gene delivery vectors based on human immunodeficiency virus type-1 (HIV-1) capable of stably coexpressing the HTLV-1 or -2taxand eGFP reporter genes in primary human cells. Transduction frequencies of up to 50%, as assessed by eGFP expression, can be achieved in human monocyte-derived macrophages and in explanted cultures of human microglia. Preliminary data suggest that Tax1expression is sufficient to up-regulate the proinflammatory cytokine profile in explanted human microglial cells. Future experiments will compare and evaluate the effect oftax1andtax2gene expression on the cellular proinflammatory cytokine expression profile, as well as demonstrate the effects of transducing human fetal astrocytes and PBMC-derived macrophages.