Comparative magnitude of cross-strain conservation of HIV variable loop neutralization epitopes.
Comparative magnitude of cross-strain conservation of HIV variable loop neutralization epitopes.
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DOI：
10.1371/journal.pone.0015994
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发表时间：
2010-12-29
期刊：
影响因子：
3.7
通讯作者：
Cardozo T
中科院分区：
文献类型：
--
作者：
Swetnam J;Shmelkov E;Zolla-Pazner S;Cardozo T
尽管人类免疫缺陷病毒（HIV-1）表面包膜糖蛋白（gp 120）的序列可变环可表现出良好的免疫原性，但已证明难以表征这些环内的保守（不变）跨株中和表位。我们最近开发了一种方法，以获得敏感和特异性的签名图案的三维（3D）形状的HIV-1中和表位的第三个可变（V3）环的gp 120的人单克隆抗体（mAb）识别。我们使用特征基序方法来估计这些表位在全球流行的HIV-1毒株中的保守性。抗V3环中和mAb 3074靶向的表位存在于87%的循环菌株中，在所有亚型中几乎均匀分布。其他抗V3 Ab的结果为：3791，存在于63%的主要非B亚型中; 2219，存在于56%的所有亚型菌株中; 2557，存在于52%的所有亚型菌株中; 447- 52 D，存在于11%的主要B亚型菌株中; 537- 10 D，存在于9%的主要B亚型菌株中;和268-D，存在于5%的主要亚型B菌株中。该估计值与这些mAb针对不同病毒组的体外试验相关。因此，mAb 3074靶向在循环HIV-1毒株中几乎完全保守的表位，证明存在隐藏在gp 120中的动态和序列可变V3环中的不变结构。由于一些可变环区是天然免疫原性的，设计免疫原以模拟其保守表位可能是一种有前途的疫苗发现方法。我们的研究结果提出了一种量化和比较保护程度的方法。
Although the sequence variable loops of the human immunodeficiency virus' (HIV-1) surface envelope glycoprotein (gp120) can exhibit good immunogenicity, characterizing conserved (invariant) cross-strain neutralization epitopes within these loops has proven difficult. We recently developed a method to derive sensitive and specific signature motifs for the three-dimensional (3D) shapes of the HIV-1 neutralization epitopes in the third variable (V3) loop of gp120 that are recognized by human monoclonal antibodies (mAbs). We used the signature motif method to estimate the conservation of these epitopes across circulating worldwide HIV-1 strains. The epitope targeted by the anti-V3 loop neutralizing mAb 3074 is present in 87% of circulating strains, distributed nearly evenly among all subtypes. The results for other anti-V3 Abs are: 3791, present in 63% of primarily non-B subtypes; 2219, present in 56% of strains across all subtypes; 2557, present in 52% across all subtypes; 447-52D, present in 11% of primarily subtype B strains; 537-10D, present in 9% of primarily subtype B strains; and 268-D, present in 5% of primarily subtype B strains. The estimates correlate with in vitro tests of these mAbs against diverse viral panels. The mAb 3074 thus targets an epitope that is nearly completely conserved among circulating HIV-1 strains, demonstrating the presence of an invariant structure hidden in the dynamic and sequence-variable V3 loop in gp120. Since some variable loop regions are naturally immunogenic, designing immunogens to mimic their conserved epitopes may be a promising vaccine discovery approach. Our results suggest one way to quantify and compare the magnitude of the conservation.
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