Ali Ayub, Ng Hwee L, Dagarag Mirabelle D, Yang Otto O
AIDS Institute, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Eur J Immunol. 2005 Nov;35(11):3221-8. doi: 10.1002/eji.200535053.
Nef expression is not required for HIV-1 replication and is highly targeted by CD8+ CTL, raising the question of why Nef expression is not lost in order to evade immunity in vivo. We explore whether MHC class I (MHC-I) down-regulation to evade CTL in general is a selective pressure maintaining Nef. HIV-1 with functional Nef (wild type, WT) is compared to virus containing a Nef point mutation (M20A) that selectively ablates MHC-I down-regulation. WT-infected cells are relatively resistant to cytolysis and less suppressed for viral replication by Gag- and RT-specific CTL compared to M20A. These viruses grow similarly in vitro in the absence of CTL, but the presence of Gag- or RT-specific CTL strongly favors WT overgrowth of M20A. Finally, while in vitro selection by Nef-specific CTL readily drives disruption of the nef reading frame, the addition of Gag- or RT-specific CTL markedly limits such escape. These data indicate that MHC-I down-regulation is an important function favoring Nef maintenance due to a net selective advantage in the setting of the general CTL response.
Nef的表达对于HIV-1复制并非必需，且是CD8⁺CTL的高度靶向目标，这就引发了一个问题：为何Nef的表达没有丢失以在体内逃避免疫。我们探究了一般情况下通过下调MHC I类分子（MHC-I）来逃避免疫细胞毒性T淋巴细胞（CTL）是否是维持Nef的一种选择压力。将具有功能性Nef的HIV-1（野生型，WT）与含有选择性消除MHC-I下调功能的Nef点突变（M20A）的病毒进行比较。与M20A相比，WT感染的细胞对细胞溶解相对具有抗性，并且被Gag和逆转录酶（RT）特异性CTL对病毒复制的抑制作用较小。在没有CTL的情况下，这些病毒在体外生长相似，但Gag或RT特异性CTL的存在强烈有利于WT而非M20A的过度生长。最后，虽然Nef特异性CTL在体外的选择很容易导致nef阅读框的破坏，但添加Gag或RT特异性CTL会显著限制这种逃逸。这些数据表明，由于在一般CTL反应的背景下具有净选择优势，下调MHC-I是有利于维持Nef的一项重要功能。
