Ali Ayub, Pillai Satish, Ng Hwee, Lubong Rachel, Richman Douglas D, Jamieson Beth D, Ding Yan, McElrath M Juliana, Guatelli John C, Yang Otto O
Department of Medicine and AIDS Institute, Center for Health Sciences, University of California, Los Angeles, CA 90095, USA.
J Immunol. 2003 Oct 15;171(8):3999-4005. doi: 10.4049/jimmunol.171.8.3999.
Nef is an HIV-1 protein that is absent in most retroviruses, yet its reading frame is highly maintained despite frequent targeting by CD8(+) CTL in vivo. Because Nef is not necessarily required for viral replication, this consistent maintenance suggests that Nef plays an important role(s) and substantial fitness constraints prevent its loss in vivo. The ability of Nef to down-regulate cell surface MHC class I (MHC-I) molecules and render infected cells resistant to CTL in general is likely to be an important contributing function. We demonstrate that mutational escape of HIV-1 from Nef-specific CTL in vitro leads to progeny virions that are increased in their susceptibility to CTL of specificities for proteins other than Nef. The escape mutants contain multiple nef mutations that impair the ability of the virus to down-regulate MHC-I through disruption of its reading frame as well as epitope point mutations. Given the rarity of nef frameshifts in vivo, these data support the concept that the ability to down-regulate MHC-I could be a key constraint for preservation of Nef in vivo.
Nef是一种HIV-1蛋白，在大多数逆转录病毒中不存在，然而尽管在体内CD8(+) CTL频繁靶向其阅读框，它仍高度保守。由于病毒复制不一定需要Nef，这种持续的保守表明Nef发挥着重要作用，并且强大的适应性限制阻止了它在体内的缺失。Nef下调细胞表面MHC I类（MHC-I）分子并使感染细胞总体上对CTL产生抗性的能力可能是一个重要的促成功能。我们证明，HIV-1在体外从Nef特异性CTL的突变逃逸导致子代病毒体对除Nef之外的蛋白质特异性CTL的敏感性增加。逃逸突变体包含多个nef突变，这些突变通过破坏其阅读框以及表位点突变损害病毒下调MHC-I的能力。鉴于体内nef移码的罕见性，这些数据支持下调MHC-I的能力可能是Nef在体内保存的关键限制这一概念。
