CD4 and major histocompatibility complex class I downregulation by the human immunodeficiency virus type 1 Nef protein in pediatric AIDS progression
CD4 and major histocompatibility complex class I downregulation by the human immunodeficiency virus type 1 Nef protein in pediatric AIDS progression
复制标题
DOI：
10.1128/jvi.77.21.11536-11545.2003
复制
发表时间：
2003-11-01
影响因子：
5.4
通讯作者：
Doria, M
中科院分区：
文献类型：
--
作者：
Casartelli, N;Di Matteo, G;Doria, M
人类免疫缺陷病毒1型（HIV-1）nef基因是艾滋病疾病进展的关键决定因素。尽管Nef蛋白具有几种体外活性，但确定体内致病性的关键活性仍然是难以捉摸的。在这项研究中，我们检测了来自13名围产期感染儿童的不同时间点的大量nef等位基因，这些儿童表现出不同的进展率：6名非进展者（NP），3名缓慢进展者（SP）和4名快速进展者（R-Ps）。分析患者来源的nef等位基因的Nef蛋白的稳态表达，其下调CD 4和主要组织相容性复合物I类（MHC-I）的细胞表面表达的相对能力，以及其结合网格蛋白接头AP-1复合物的能力。我们发现，与从SP和RP分离的nef等位基因相比，NP衍生的nef等位基因具有降低的CD 4和MHC-I下调活性。与此相反，SP和RP衍生的nef等位基因没有不同，有效地下调CD 4和MHC-I。AP-1结合是与临床进展无关的主要nef等位基因的保守功能。来自NP的缺陷Nef蛋白，而不是在其序列中共享共同的特定变化，积累了各种氨基酸取代，主要位于先前与Nef生物学特性相关的保守结构域之外。我们的数据表明，Nef介导的细胞表面CD 4和MHC-I的下调显著有助于HIV-1致病潜力的表达。
The human immunodeficiency virus type 1 (HIV-1) nef gene is a crucial determinant in AIDS disease progression. Although several in vitro activities have been attributed to the Nef protein, identifying the one critical for in vivo pathogenicity remains elusive. In this study, we examined a large number of nef alleles derived at various time points from 13 perinatally infected children showing different progression rates: six nonprogressors (NPs), three slow progressors; (SPs), and four rapid progressors (R-Ps). The patient-derived nef alleles were analyzed for their steady-state expression of a Nef protein, for their relative ability to downregulate cell surface expression of CD4 and major histocompatibility complex class I (MHC-I) and for their capacity to bind the clathrin adaptor AP-1 complex. We found that NP-derived nef alleles, compared to nef alleles isolated from SPs and RPs, had reduced CD4 and MHC-I downregulation activities. In contrast, SP- and RP-derived nef alleles did not differ and efficiently downregulated both CD4 and MHC-I. AP-1 binding was a conserved function of primary nef alleles not correlated with clinical progression. Defective Nef proteins from NPs, rather than sharing common specific changes in their sequences, accumulated various amino acid substitutions, mainly located outside the conserved domains previously associated with Nef biological properties. Our data indicate that Nef-mediated downregulation of cell surface CD4 and MHC-I significantly contributes to the expression of the pathogenic potential of HIV-1.