Milich L, Margolin B H, Swanstrom R
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill 27599, USA.
Virology. 1997 Dec 8;239(1):108-18. doi: 10.1006/viro.1997.8821.
The V3 domain plays a central role in the biology of the HIV-1 Env glycoprotein gp 120 as a dominant target for neutralizing antibodies for some HIV-1 isolates, and as a major determinant in the switch from the nonsyncytium-inducing (NSI) to the syncytium-inducing (SI) form of HIV-1 that is associated with accelerated disease progression. Basic amino acid substitutions are known to play an important role in the SI phenotype. We have used the presence of basic amino acid substitutions in V3 sequences to divide sequences in a large data base into SI-like and NSI-like. We found significant differences in features of sequence variability between these two groups of sequences. Of the thirty-six most frequent substitutions in V3, twenty appear disproportionately among either the SI-like sequences or the NSI-like sequences. The fourteen favored substitutions among the SI-like sequences account for 50% of the twofold increased variability seen in this group. In addition, we found a linked change within the CD4-binding domain of gp 120 downstream of V3. These differences are interpreted in the context of structure, function, and selective pressure. An understanding of these patterns of sequence variability offers the possibility of designing a degenerate SI-specific V3 immunogen to use as a therapeutic vaccine with the hope of slowing or preventing the appearance of SI variants.
V3结构域在HIV-1包膜糖蛋白gp120的生物学特性中起着核心作用，它是一些HIV-1分离株中和抗体的主要靶点，也是HIV-1从非融合诱导型（NSI）向融合诱导型（SI）转变的主要决定因素，而这种转变与疾病进展加速相关。已知碱性氨基酸取代在SI表型中起重要作用。我们利用V3序列中碱性氨基酸取代的存在，将一个大型数据库中的序列分为SI样和NSI样。我们发现这两组序列在序列变异性特征上存在显著差异。在V3中36个最常见的取代中，有20个在SI样序列或NSI样序列中出现的比例不均衡。SI样序列中14个偏好的取代占该组中观察到的变异性增加两倍的50%。此外，我们在V3下游的gp120的CD4结合域内发现了一个连锁变化。这些差异在结构、功能和选择压力的背景下进行了解释。对这些序列变异性模式的理解为设计一种简并的SI特异性V3免疫原提供了可能性，该免疫原可作为治疗性疫苗使用，有望减缓或预防SI变体的出现。
