Human immunodeficiency virus type 1 V1-V2 envelope loop sequences expand and add glycosylation sites over the course of infection, and these modifications affect antibody neutralization sensitivity
Human immunodeficiency virus type 1 V1-V2 envelope loop sequences expand and add glycosylation sites over the course of infection, and these modifications affect antibody neutralization sensitivity
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DOI：
10.1128/jvi.00141-06
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发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Overbaugh, Julie
中科院分区：
文献类型：
--
作者：
Sagar, Manish;Wu, Xueling;Overbaugh, Julie
在感染过程中，人类免疫缺陷病毒1型（HIV-1）不断适应以逃避进化的宿主中和抗体反应。包膜可变环序列的变化，特别是糖基化的程度，与抗体逃逸有关。为了记录可能影响抗体敏感性的修饰，我们比较了9名患有HIV-1亚型a的妇女在感染初期分离的多个序列中的包膜可变环I和2 （V1-V2）与在感染慢性期约2至3年分离的包膜可变环I和2 （V1-V2）。在慢性感染期间分离的HIV-1序列具有明显更长的V1-V2环，具有明显更多的潜在n链糖基化位点。比感染早期分离的序列要好。为了评估这些V1-V2变化对抗体中和和传染性的影响，我们创建了嵌合包膜序列，将受试者的V1-V2序列整合到常见亚型a包膜主干中，然后使用它们生成假型病毒。与亲本病毒相比，引入受试者早期感染的V1-V2包膜可变环使嵌合包膜对受试者的血浆样本更敏感，但仅对分离序列6个月后收集的血浆样本更敏感。将早期感染的V1-V2序列替换为慢性感染的V1-V2序列时，在相同的血浆中未检测到中和作用，这表明V1-V2的变化有助于抗体逃逸。然而，来自不同感染时间的带有V1-V2片段的假型病毒对异源池血浆的中和敏感性没有显著差异，这表明来自感染早期的带有V1-V2环的病毒本身并不具有更高的中和敏感性。携带嵌合包膜的假型病毒在早期感染的V1-V2序列中能更有效地感染低CD4浓度的细胞，而在慢性感染过程中分离的带有V1-V2序列的工程病毒在感染低CCR5浓度的细胞方面表现得稍好。这些研究表明，在感染过程中，V1-V2包膜结构域的变化会影响对自体中和抗体的敏感性，也可能影响宿主受体/辅助受体的相互作用。
Over the course of infection, human immunodeficiency virus type 1 (HIV-1) continuously adapts to evade the evolving host neutralizing antibody responses. Changes in the envelope variable loop sequences, particularly the extent of glycosylation, have been implicated in antibody escape. To document modifications that potentially influence antibody susceptibility, we compared envelope variable loops I and 2 (V1-V2) from multiple sequences isolated at the primary phase of infection to those isolated around 2 to 3 years into the chronic phase of infection in nine women with HIV-1 subtype A. HIV-1 sequences isolated during chronic infection had significantly longer V1-V2 loops, with a significantly higher number of potential N-linked glycosylation sites, than the sequences isolated early in infection. To assess the effects of these V1-V2 changes on antibody neutralization and infectivity, we created chimeric envelope sequences, which incorporated a subject's V1-V2 sequences into a common subtype A envelope backbone and then used them to generate pseudotyped viruses. Compared to the parent virus, the introduction of a subject's early-infection V1-V2 envelope variable loops rendered the chimeric envelope more sensitive to that subject's plasma samples but only to plasma samples collected > 6 months after the sequences were isolated. Neutralization was not detected with the same plasma when the early-infection V1-V2 sequences were replaced with chronic-infection V1-V2 sequences, suggesting that changes in V1-V2 contribute to antibody escape. Pseudotyped viruses with V1-V2 segments from different times in infection, however, showed no significant difference in neutralization sensitivity to heterologous pooled plasma, suggesting that viruses with V1-V2 loops from early in infection were not inherently more neutralization sensitive. Pseudotyped viruses bearing chimeric envelopes with early-infection V1-V2 sequences showed a trend in infecting cells with low CD4 concentrations more efficiently, while engineered viruses with V1-V2 sequences isolated during chronic infection were moderately better at infecting cells with low CCR5 concentrations. These studies suggest that changes within the V1-V2 envelope domains over the course of an infection influence sensitivity to autologous neutralizing antibodies and may also impact host receptor/coreceptor interactions.