Human immunodeficiency virus type 1 subtype B ancestral envelope protein is functional and elicits neutralizing antibodies in rabbits similar to those elicited by a circulating subtype B envelope
Human immunodeficiency virus type 1 subtype B ancestral envelope protein is functional and elicits neutralizing antibodies in rabbits similar to those elicited by a circulating subtype B envelope
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DOI：
10.1128/jvi.79.17.11214-11224.2005
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发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Mullins, JI
中科院分区：
文献类型：
--
作者：
Doria-Rose, NA;Learn, GH;Mullins, JI
人类免疫缺陷病毒1型(HIV-1)是疫苗开发的一个困难目标，部分原因是它的遗传多样性不断扩大，并伴随着逃避免疫识别的能力。疫苗效力可以通过最大限度地提高免疫原抗原与疫苗接种者可能遇到的病毒的相似性来提高。为此，我们设计了一种原型HIV-1包膜疫苗，使用推断的env基因的祖先状态。通过计算机模拟表明，祖先状态重建方法的准确率为95%，当估计在恒河猴实验感染研究中使用的已知接种量时，准确率为99.8%。此外，推断出的祖先基因与用于推导祖先的序列集平均相差12.3%，而用于推导祖先基因的序列彼此之间平均相差17.3%。构建了人类B亚型HIV-1全长env基因，编码160 kDa的糖蛋白，与表达HIV-1辅受体CCR5的细胞结合并融合。该Env在病毒假型分析中也具有功能。当用gp160或gp140表达载体和重组gp120以DNA主蛋白Boost方案免疫兔时，人工基因诱导的免疫球蛋白G抗体能够弱中和异源HIV-1原代毒株。与自然分离株HIV-1 SF162平行免疫的兔子的结果相似。进一步的设计努力，以更好地呈现保守的中和决定因素是有必要的。
Human immunodeficiency virus type 1 (HIV-1) is a difficult target for vaccine development, in part because of its ever-expanding genetic diversity and attendant capacity to escape immunologic recognition. Vaccine efficacy might be improved by maximizing immunogen antigenic similarity to viruses likely to be encountered by vaccinees. To this end, we designed a prototype HIV-1 envelope vaccine using a deduced ancestral state for the env gene. The ancestral state reconstruction method was shown to be > 95% accurate by computer simulation and 99.8% accurate when estimating the known inoculum used in an experimental infection study in rhesus macaques. Furthermore, the deduced ancestor gene differed from the set of sequences used to derive the ancestor by an average of 12.3%, while these latter sequences were an average of 17.3% different from each other. A full-length ancestral subtype B HIV-1 env gene was constructed and shown to produce a glycoprotein of 160 kDa that bound and fused with cells expressing the HIV-1 coreceptor CCR5. This Env was also functional in a virus pseudotype assay. When either gp160- or gp140-expressing plasmids and recombinant gp120 were used to immunize rabbits in a DNA prime-protein boost regimen, the artificial gene induced immunoglobulin G antibodies capable of weakly neutralizing heterologous primary HIV-1 strains. The results were similar for rabbits immunized in parallel with a natural isolate, HIV-1 SF162. Further design efforts to better present conserved neutralization determinants are warranted.