Type-specific epitopes targeted by monoclonal antibodies with exceptionally potent neutralizing activities for selected strains of human immunodeficiency virus type 1 map to a common region of the V2 domain of gp120 and differ only at single positions from the clade B consensus sequence
Type-specific epitopes targeted by monoclonal antibodies with exceptionally potent neutralizing activities for selected strains of human immunodeficiency virus type 1 map to a common region of the V2 domain of gp120 and differ only at single positions from the clade B consensus sequence
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DOI：
10.1128/jvi.02054-06
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发表时间：
2007-02-01
影响因子：
5.4
通讯作者：
Pinter, A.
中科院分区：
文献类型：
--
作者：
Honnen, W. J.;Krachmarov, C.;Pinter, A.
只有少数单克隆抗体（MAb）已被分离出来，识别人类免疫缺陷病毒1型（HIV-1）Env蛋白的保守位点，并具有广泛的中和活性。已经描述了针对Env的各个结构域中的靶标的其他MAb，其是强中和的，但它们具有有限的宽度。一种这样的MAb，2909，具有特异性针对SF 162 Env上的四级表位的独特有效的中和活性，其需要V2和V3结构域两者的存在。我们现在表明，替换SF 162 V3序列与共识V3序列的多个亚型导致减弱，但仍然有效的中和2909和2909的类型特异性的主要决定因素驻留在V2域。160位的取代完全消除了2909的反应性，167位的突变减弱或增强了该抗体的中和作用。V2中相同位置处的不同取代先前显示引入由MAb 10/76 b和C108 g识别的表位，并允许这些MAb的有效中和。在JR-FL Env的V2结构域中的关键位置处的两个取代也允许2909表位的有效表达，并且YU 2 V2中的单个取代足以表达2909、C108 g和10/76 b表位。这些结果表明，2909、C108 g和10/76 B的最小表位仅在单个位置与进化枝B共有序列的最小表位不同，并表明所有三种单克隆抗体识别V2中相对保守序列的不同变体，V2是HfV-1中和的特别敏感的介体。
Only a few monoclonal antibodies (MAbs) have been isolated that recognize conserved sites in human immunodeficiency virus type 1 (HIV-1) Env proteins and possess broad neutralizing activities. Other MAbs directed against targets in various domains of Env have been described that are strongly neutralizing, but they possess limited breadth. One such MAb, 2909, possesses a uniquely potent neutralizing activity specific for a quaternary epitope on SF162 Env that requires the presence of both the V2 and the V3 domains. We now show that replacement of the SF162 V3 sequence with consensus V3 sequences of multiple subtypes led to attenuated but still potent neutralization by 2909 and that the main determinants for the type specificity of 2909 reside in the V2 domain. A substitution at position 160 completely eliminated 2909 reactivity, and mutations at position 167 either attenuated or potentiated neutralization by this antibody. Different substitutions at the same positions in V2 were previously shown to introduce epitopes recognized by MAbs 10/76b and C108g and to allow potent neutralization by these MAbs. Two substitutions at key positions in the V2 domain of JR-FL Env also allowed potent expression of the 2909 epitope, and single substitutions in YU2 V2 were sufficient for expression of the 2909, C108g, and 10/76b epitopes. These results demonstrate that the minimal epitopes for 2909, C108g, and 10/76b differed from that of the clade B consensus sequence only at single positions and suggest that all three MAbs recognize distinct variants of a relatively conserved sequence in V2 that is a particularly sensitive mediator of HfV-1 neutralization.