Merat R, Raoul H, Leste-Lasserre T, Sonigo P, Pancino G
Génétique des Virus (ICGM-CNRS UPR0415), Institut Cochin de Génétique Moléculaire, 75014 Paris, France.
J Virol. 1999 Jul;73(7):5698-706. doi: 10.1128/JVI.73.7.5698-5706.1999.
Lentiviruses have in their transmembrane glycoprotein (TM) a highly immunogenic structure referred to as the principal immunodominant domain (PID). The PID forms a loop of 5 to 7 amino acids between two conserved cysteines. Previous studies showed that envelope (Env) glycoprotein functions of feline immunodeficiency virus (FIV) could be retained after extensive mutation of the PID loop sequence, in spite of its high conservation. In order to compare Env function in different lentiviruses, either random mutations were introduced in the PID loop sequence of human immunodeficiency virus type 1 (HIV-1) or the entire HIV-1 PID loop was replaced by the corresponding PID loop of FIV or simian immunodeficiency virus (SIV). In the macrophage-tropic HIV-1 ADA Env, mutations impaired the processing of the gp160 Env precursor, thereby abolishing viral infectivity. However, 6 of the 108 random Env mutants that were screened retained the capacity to induce cell membrane fusion. The SIV and FIV sequences and five random mutations were then introduced in the context of T-cell-line-adapted HIV-1 LAI which, although phenotypically distant from HIV-1 ADA, has an identical PID loop sequence. In contrast to the situation for HIV-1 ADA mutants, the cleavage of the Env precursor was unaffected in most HIV-1 LAI mutants. Such mutations, however, resulted in increased shedding of the gp120 surface glycoprotein (SU) from the gp41 TM. The HIV-1 LAI Env mutants showed high fusogenic efficiency. Three Env mutants retained the capacity to mediate virus entry in target cells, although less efficiently than the wild-type Env, and allowed the reconstitution of infectious molecular clones. These results indicated that in HIV-1, like FIV, the conserved PID sequence can be changed without impairing Env function. However, functional constraints on the PID of HIV-1 vary depending on the structural context of Env, presumably in relation to the role of the PID in the interaction of the SU and TM subunits and the stability of the Env complex.
慢病毒的跨膜糖蛋白（TM）具有一种高度免疫原性的结构，称为主要免疫显性结构域（PID）。PID在两个保守的半胱氨酸之间形成一个由5至7个氨基酸组成的环。先前的研究表明，尽管猫免疫缺陷病毒（FIV）的PID环序列具有高度保守性，但在对其进行广泛突变后，包膜（Env）糖蛋白的功能仍可保留。为了比较不同慢病毒中的Env功能，要么在1型人类免疫缺陷病毒（HIV-1）的PID环序列中引入随机突变，要么用FIV或猴免疫缺陷病毒（SIV）的相应PID环替换整个HIV-1 PID环。在巨噬细胞嗜性的HIV-1 ADA Env中，突变损害了gp160 Env前体的加工过程，从而消除了病毒的感染性。然而，在筛选的108个随机Env突变体中，有6个保留了诱导细胞膜融合的能力。然后将SIV和FIV序列以及五个随机突变引入适应T细胞系的HIV-1 LAI中，尽管其表型与HIV-1 ADA不同，但其PID环序列相同。与HIV-1 ADA突变体的情况相反，大多数HIV-1 LAI突变体中Env前体的切割未受影响。然而，此类突变导致gp120表面糖蛋白（SU）从gp41 TM上的脱落增加。HIV-1 LAI Env突变体显示出高融合效率。三个Env突变体保留了介导病毒进入靶细胞的能力，尽管效率低于野生型Env，并允许重建感染性分子克隆。这些结果表明，在HIV-1中，与FIV一样，保守的PID序列可以改变而不损害Env功能。然而，HIV-1的PID的功能限制因Env的结构背景而异，这可能与PID在SU和TM亚基相互作用中的作用以及Env复合物的稳定性有关。
