Tat protein of human immunodeficiency virus type 1 subtype C strains is a defective chemokine
Tat protein of human immunodeficiency virus type 1 subtype C strains is a defective chemokine
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DOI：
10.1128/jvi.78.5.2586-2590.2004
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发表时间：
2004-03-01
影响因子：
5.4
通讯作者：
Prasad, VR
中科院分区：
文献类型：
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作者：
Ranga, U;Shankarappa, R;Prasad, VR
人类免疫缺陷病毒1型（HIV-1）相关痴呆（HAD）与单核细胞向大脑迁移的增加有关，在其他无症状的受试者中，印度的HAD发病率似乎低于美国和欧洲（1 - 2%对15 - 30%）。由于在这些区域传播的HIV-1毒株之间存在遗传差异，我们试图确定与这种差异相关的病毒决定因素。鉴于Tat蛋白与单核细胞趋化功能的关联，我们将其作为这些研究的目标。对代表9个亚型的Tat序列的分析显示，在C Tat亚型（C-Tat）中至少有6个氨基酸残基是差异保守的。其中，半胱氨酸（31位）在非C亚型病毒中高度保守（约99%），超过90%的C亚型病毒编码丝氨酸。我们假设C-Tat的趋化功能由于CC基序的破坏而受到损害，并使用野生型C-Tat （CS）及其通过定点突变衍生的两个等基因变体（CC和SC）进行了测试。我们发现CS天然变体在单核细胞趋化活性方面存在缺陷，但在交易激活特性方面没有损失。CC突变体在这两种功能上都有能力，而SC突变体在这两种功能上都有缺陷。因此，C-Tat趋化特性的丧失可能是HAD发病率降低的原因；虽然没有提供确凿的证据，但这项研究首次提供了与C亚型病毒生物学差异相关的潜在流行病学现象的证据。
Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is correlated with increased monocyte migration to the brain, and the incidence of HAD among otherwise asymptomatic subjects appears to be lower in India than in the United States and Europe (1 to 2% versus 15 to 30%). Because of the genetic differences between HIV-1 strains circulating in these regions, we sought to identify viral determinants associated with this difference. We targeted Tat protein for these studies in view of its association with monocyte chemotactic function. Analyses of Tat sequences representing nine subtypes revealed that at least six amino acid residues are differentially conserved in subtype C Tat (C-Tat). Of these, cysteine (at position 31) was highly (>99%) conserved in non-subtype C viruses and more than 90% of subtype C viruses encoded a serine. We hypothesized a compromised chemotactic function of C-Tat due to the disruption of CC motif and tested it with the wild type C-Tat (CS) and its two isogenic variants (CC and SC) derived by site-directed mutagenesis. We found that the CS natural variant was defective for monocyte chemotactic activity without a loss in the transactivation property. While the CC mutant is functionally competent for both the functions, in contrast, the SC mutant was defective in both. Therefore, the loss of the C-Tat chemotactic property may underlie the reduced incidence of HAD; although not presenting conclusive evidence, this study provides the first evidence for a potential epidemiologic phenomenon associated with biological differences in the subtype C viruses.