Antibody neutralization escape mediated by point mutations in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41
Antibody neutralization escape mediated by point mutations in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41
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DOI：
10.1128/jvi.79.4.2097-2107.2005
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发表时间：
2005-02-01
影响因子：
5.4
通讯作者：
Montelaro, RC
中科院分区：
文献类型：
--
作者：
Kalia, V;Sarkar, S;Montelaro, RC
人类免疫缺陷病毒1型（HIV-1）感染的持久性在强大的宿主免疫力的存在下，已部分与病毒包膜蛋白的变异，导致抗原变异和逃避中和抗体。先前对天然中和逃逸突变体的研究主要集中在gp 120和gp 41胞外域序列变异上，这些变异通过改变Env的构象或糖基化模式来改变抗体结合，这可能是由于施加在糖蛋白的暴露胞外域组分上的免疫压力。在这里，我们第一次展示了一种新的机制，通过这种机制，包膜的跨膜成分（gp 41）的胞浆内尾部的点突变可以使病毒对单克隆抗体和广泛中和的多克隆血清抗体的中和具有抗性。胞质内尾内高度保守的结构基序中的点突变导致中和抗体与Env胞外域的结合减少，这显然是由于gp 41胞外域和gp 120中的变构变化。虽然突变病毒的受体结合和感染性保持不变，但Env抗原性的变化与突变病毒的中和抗性增加有关。这些研究证明了gp 120和gp 41的结构整合的性质，并强调了以前未认识到的潜在的关键作用，即使是微小的序列变化的胞质内尾在调节HIV-1包膜糖蛋白复合物的胞外域的抗原性。
The persistence of human immunodeficiency virus type 1 (HIV-1) infection in the presence of robust host immunity has been associated in part with variation in viral envelope proteins leading to antigenic variation and escape from neutralizing antibodies. Previous studies of natural neutralization escape mutants have predominantly focused on gp120 and gp41 ectodomain sequence variations that alter antibody binding via changes in conformation or glycosylation pattern of the Env, likely due to the immune pressure exerted on the exposed ectodomain component of the glycoprotein. Here, we show for the first time a novel mechanism by which point mutations in the intracytoplasmic tail of the transmembrane component (gp41) of envelope can render the virus resistant to neutralization by monoclonal antibodies and broadly neutralizing polyclonal serum antibodies. Point mutations in a highly conserved structural motif within the intracytoplasmic tail resulted in decreased binding of neutralizing antibodies to the Env ectodomain, evidently due to allosteric changes both in the gp41 ectodomain and in gp120. While receptor binding and infectivity of the mutant virus remained unaltered, the changes in Env antigenicity were associated with an increase in neutralization resistance of the mutant virus. These studies demonstrate the structurally integrated nature of gp120 and gp41 and underscore a previously unrecognized potentially critical role for even minor sequence variation of the intracytoplasmic tail in modulating the antigenicity of the ectodomain of HIV-1 envelope glycoprotein complex.