A Multivalent Clade C HIV-1 Env Trimer Cocktail Elicits a Higher Magnitude of Neutralizing Antibodies than Any Individual Component
A Multivalent Clade C HIV-1 Env Trimer Cocktail Elicits a Higher Magnitude of Neutralizing Antibodies than Any Individual Component
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DOI：
10.1128/jvi.03331-14
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发表时间：
2015-03-01
影响因子：
5.4
通讯作者：
Barouch, Dan H.
中科院分区：
文献类型：
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作者：
Bricault, Christine A.;Kovacs, James M.;Barouch, Dan H.
人类免疫缺陷病毒1型(HIV-1)的序列多样性给HIV-1疫苗的研制带来了巨大的挑战。解决这种序列多样性和提高中和抗体(NAB)大小的一种策略是利用HIV-1包膜(Env)免疫原的多价混合物。在这里，我们报告了三个新的急性分支HIV-1环境gp140三聚体(459C、405C和939C)的产生和特征，每个三聚体都具有独特的抗原性。在测试的单个三聚体中，459C在接种疫苗的豚鼠中引发了最有效的NAB反应。我们评估了不同的Clade C Env Trimer混合物的免疫原性，发现与任何单一的Clade C三聚体相比，Clade C三聚体的四价鸡尾酒对一组1A和1B级病毒产生了更多的NAB，表明该混合物比鸡尾酒的所有单独成分都有优势。这些数据表明，用C-Env三聚体的混合物接种是一种很有前途的策略，可以增强疫苗诱导的NAB反应。重要的是，目前尚不清楚如何通过接种产生针对不同循环中的HIV-1 Env的有效NAB。解决这种多样性的一种策略是利用不同的可溶HIV-1包膜蛋白的混合物。在这项研究中，我们产生并鉴定了三种不同的、新颖的、急性的C类可溶三聚体。我们用单一的三聚体和混合的三聚体给豚鼠接种疫苗，我们发现四个三聚体的混合物比混合物中的任何一个三聚体都能产生更多的NAB。这项研究的结果表明，进一步开发环境三聚体鸡尾酒是有必要的。
The sequence diversity of human immunodeficiency virus type 1 (HIV-1) presents a formidable challenge to the generation of an HIV-1 vaccine. One strategy to address such sequence diversity and to improve the magnitude of neutralizing antibodies (NAbs) is to utilize multivalent mixtures of HIV-1 envelope (Env) immunogens. Here we report the generation and characterization of three novel, acute clade C HIV-1 Env gp140 trimers (459C, 405C, and 939C), each with unique antigenic properties. Among the single trimers tested, 459C elicited the most potent NAb responses in vaccinated guinea pigs. We evaluated the immunogenicity of various mixtures of clade C Env trimers and found that a quadrivalent cocktail of clade C trimers elicited a greater magnitude of NAbs against a panel of tier 1A and 1B viruses than any single clade C trimer alone, demonstrating that the mixture had an advantage over all individual components of the cocktail. These data suggest that vaccination with a mixture of clade C Env trimers represents a promising strategy to augment vaccine-elicited NAb responses.IMPORTANCEIt is currently not known how to generate potent NAbs to the diverse circulating HIV-1 Envs by vaccination. One strategy to address this diversity is to utilize mixtures of different soluble HIV-1 envelope proteins. In this study, we generated and characterized three distinct, novel, acute clade C soluble trimers. We vaccinated guinea pigs with single trimers as well as mixtures of trimers, and we found that a mixture of four trimers elicited a greater magnitude of NAbs than any single trimer within the mixture. The results of this study suggest that further development of Env trimer cocktails is warranted.