Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice
Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice
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DOI：
10.1016/s0092-8674(00)81748-1
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发表时间：
1998-10-16
期刊：
影响因子：
64.5
通讯作者：
Jolicoeur, P
中科院分区：
文献类型：
--
作者：
Hanna, Z;Kay, DG;Jolicoeur, P
在CD4(+)T细胞和巨噬细胞/树突状细胞系的细胞中表达HIV-1完整编码序列的转基因(TG)小鼠会出现严重的艾滋病样病理：无法茁壮成长/体重减轻、腹泻、消瘦、过早死亡、胸腺萎缩、CD4(+)T细胞丧失、间质性肺炎和小管间质性肾炎。表达选择的HIV-1基因的转基因小鼠(S)的产生揭示了NEF含有一个主要的疾病决定因素。疾病的潜伏期和进展(快/慢)与TG的表达水平密切相关。表达NEF的TG胸腺细胞被激活，α-CD3对包括LAT和MAPK在内的几种底物的酪氨酸磷酸化反应强烈。这个小鼠模型与人类艾滋病，特别是儿童艾滋病相似，表明Nef可能在人类艾滋病中发挥关键作用，而不是它在病毒复制中的作用。
Transgenic (Tg) mice expressing the complete coding sequences of HIV-1 in CD4(+) T cells and in cells of the macrophage/dendritic lineages develop severe AIDS-like pathologies: failure to thrive/weight loss, diarrhea, wasting, premature death, thymus atrophy, loss of CD4(+) T cells, interstitial pneumonitis, and tubulo-interstitial nephritis. The generation of Tg mice expressing selected HIV-1 gene(s) revealed that nef harbors a major disease determinant. The latency and progression (fast/slow) of the disease were strongly correlated with the levels of Tg expression. Nef-expressing Tg thymocytes were activated and alpha-CD3 hyperresponsive with respect to tyrosine phosphorylation of several substrates, including LAT and MAPK. The similarity of this mouse model to human AIDS, particularly pediatric AIDS, suggests that Nef may play a critical role in human AIDS, independently of its role in virus replication.