Genotypic and phenotypic characterization of a neutralization-resistant breakthrough population of HIV-1.
Genotypic and phenotypic characterization of a neutralization-resistant breakthrough population of HIV-1.
复制标题
HIV-1 中和抗性突破群体的基因型和表型特征。
DOI：
10.1006/viro.1996.0184
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Ehrlich,GD
中科院分区：
文献类型：
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作者：
Sirko,DA;Ehrlich,GD
HIV-1 的某些抗体中和突变体图谱位于抗体识别表位之外，从而表明非线性构象域的存在。为了开始定义 HIV 包膜蛋白的相互作用区域，HIV-1 的中和敏感克隆 HXB2/BH10Sal-Bam 在 V3 特异性单克隆抗体 0.5β 存在的情况下进行传代。对突破性病毒群体 V3 结构域的 DNA 序列分析揭示了一个保留亲本 V3 基因型的群体。对这一突破性群体的定量 DNA 序列分析揭示了与 V3 不相邻的几个包膜结构域中存在突变“热点”。在 gp41 和 gp120 的 C1、V1/V2、C2 和 C5 结构域中均发现突变。相比之下，gp120、C3、V4、C4和V5的其他区域完全没有变化。在 V1 中，14 个氨基酸序列中的三个残基经历了 5 次取代，而在 C5 中，7 个氨基酸序列中的三个残基经历了 4 次取代。这一发现表明，特定结构域（V1/V2、C5 和 gp41）中聚集的某些残基在特定的环境应激源下经历了多次取代，表明 HIV 包膜表现出的适应性可塑性程度是有限的。基于这一观察，使用针对各种包膜表位的一组抗体，有可能辨别一组规则，这些规则解释了各种包膜结构域彼此之间以及与它们的环境之间的相互作用。对包膜蛋白所受到的生理限制的深入了解可能有助于制定治疗和疫苗接种策略。
Certain antibody neutralization escape mutants of HIV-1 map outside of the antibody recognition epitope, thereby suggesting the presence of nonlinear conformational domains. In an effort to begin to define the interacting regions of the HIV envelope proteins, a neutralization-sensitive clone of HIV-1, HXB2/BH10Sal-Bam, was passaged in the presence of the V3-specific monoclonal antibody 0.5β. DNA sequence analysis of the V3 domain of the breakthrough viral populations revealed one population that retained the parental V3 genotype. Quantitative DNA sequence analysis of this breakthrough population revealed the presence of mutational “hotspots” in several envelope domains that are noncontiguous with V3. Mutations were seen throughout gp41 and the C1, V1/V2, C2, and C5 domains of gp120. In contrast, other regions of gp120, C3, V4, C4, and V5 remained totally unchanged. Within V1, three residues within a 14-amino acid stretch experienced five substitutions and in C5 three residues within a 7-amino acid stretch experienced four substitutions. This finding, that certain residues clustered within particular domains (V1/V2, C5, and gp41) experienced multiple substitutions under a defined environmental stressor, suggests that the degree of adaptive plasticity exhibited by the HIV envelope is limited. Based on this observation it may be possible, using a set of antibodies to various envelope epitopes, to discern a set of rules which explain the interactions of the various envelope domains with each other and with their environment. The insight gained into the physiologic constraints that the envelope proteins are subject to may be useful in developing therapeutic and vaccination strategies.