Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment.
Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment.
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人类免疫缺陷病毒 1 型对有效靶向 CD4 附着位点的单克隆抗体 B12 的抵抗机制。
DOI：
10.1128/jvi.01142-09
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发表时间：
2009
影响因子：
5.4
通讯作者：
Mascola,JohnR
中科院分区：
文献类型：
--
作者：
Wu,Xueling;Zhou,Tongqing;O'Dell,Sijy;Wyatt,RichardT;Kwong,PeterD;Mascola,JohnR
人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白gp 120与其主要细胞受体CD 4结合的区域形成了对中和抗体的脆弱性位点。单克隆抗体b12利用CD 4结合位点的保守性和可及性来中和许多（尽管不是全部）HIV-1分离株。为了了解病毒对b12耐药的基础，我们使用b12-gp 120接触位点的原子级定义来研究一组不同的循环病毒。序列分析，计算建模和定点诱变的组合被用来确定氨基酸变体对b12结合和中和的影响。我们发现，几个取代内占主导地位的b12接触表面，称为CD 4结合环，介导的b12的阻力，这些取代居住在接近已知的CD 4接触表面。因此，病毒在接近但不是CD 4接触表面的一部分的关键b12接触残基中变化。这解释了病毒分离物如何能够逃避b12中和，同时保持与CD 4的功能性结合。此外，尽管在b12接触位点的序列变异极小，但一些病毒对b12具有耐药性。这种中和抗性通常可以通过改变被认为影响病毒包膜刺突的四级构型的残基来逆转。为了设计能引发针对CD 4结合位点的中和抗体的免疫原，研究人员需要解决gp 120这一区域内的抗原变异以及三聚体病毒包膜刺突的天然构型对CD 4结合位点的限制性访问。
The region of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 that engages its primary cellular receptor CD4 forms a site of vulnerability to neutralizing antibodies. The monoclonal antibody b12 exploits the conservation and accessibility of the CD4-binding site to neutralize many, though not all, HIV-1 isolates. To understand the basis of viral resistance to b12, we used the atomic-level definition of b12-gp120 contact sites to study a panel of diverse circulating viruses. A combination of sequence analysis, computational modeling, and site-directed mutagenesis was used to determine the influence of amino acid variants on binding and neutralization by b12. We found that several substitutions within the dominant b12 contact surface, called the CD4-binding loop, mediated b12 resistance, and that these substitutions resided just proximal to the known CD4 contact surface. Hence, viruses varied in key b12 contact residues that are proximal to, but not part of, the CD4 contact surface. This explained how viral isolates were able to evade b12 neutralization while maintaining functional binding to CD4. In addition, some viruses were resistant to b12 despite minimal sequence variation at b12 contact sites. Such neutralization resistance usually could be reversed by alterations at residues thought to influence the quaternary configuration of the viral envelope spike. To design immunogens that elicit neutralizing antibodies directed to the CD4-binding site, researchers need to address the antigenic variation within this region of gp120 and the restricted access to the CD4-binding site imposed by the native configuration of the trimeric viral envelope spike.