Bricault Christine A, Kovacs James M, Nkolola Joseph P, Yusim Karina, Giorgi Elena E, Shields Jennifer L, Perry James, Lavine Christy L, Cheung Ann, Ellingson-Strouss Katharine, Rademeyer Cecelia, Gray Glenda E, Williamson Carolyn, Stamatatos Leonidas, Seaman Michael S, Korber Bette T, Chen Bing, Barouch Dan H
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Division of Molecular Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
J Virol. 2015 Mar;89(5):2507-19. doi: 10.1128/JVI.03331-14. Epub 2014 Dec 24.
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.
It 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.
1型人类免疫缺陷病毒（HIV-1）的序列多样性对研发HIV-1疫苗构成了巨大挑战。应对这种序列多样性并提高中和抗体（NAb）水平的一种策略是利用HIV-1包膜（Env）免疫原的多价混合物。在此，我们报告了三种新型急性C亚型HIV-1 Env gp140三聚体（459C、405C和939C）的产生及特性，每种三聚体都具有独特的抗原特性。在测试的单个三聚体中，459C在接种疫苗的豚鼠中引发了最强的NAb反应。我们评估了C亚型Env三聚体各种混合物的免疫原性，发现C亚型三聚体的四价混合物针对一组1A和1B级病毒引发的NAb水平高于任何单个C亚型三聚体，这表明该混合物比混合物中的所有单个成分都具有优势。这些数据表明，接种C亚型Env三聚体混合物是增强疫苗引发的NAb反应的一种有前景的策略。
目前尚不清楚如何通过接种疫苗产生针对多种循环HIV-1 Env的强效NAb。应对这种多样性的一种策略是利用不同可溶性HIV-1包膜蛋白的混合物。在本研究中，我们产生并表征了三种不同的新型急性C亚型可溶性三聚体。我们用单个三聚体以及三聚体混合物对豚鼠进行接种，发现四种三聚体的混合物引发的NAb水平高于混合物中的任何单个三聚体。本研究结果表明Env三聚体混合物值得进一步研发。
