Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses
Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses
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DOI：
10.1016/j.celrep.2019.06.074
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发表时间：
2019-07-23
期刊：
影响因子：
8.8
通讯作者：
Zolla-Pazner, Susan
中科院分区：
文献类型：
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作者：
Hessell, Ann J.;Powell, Rebecca;Zolla-Pazner, Susan
HIV-1包膜的V1 V2区是几种广泛中和抗体（bNAb）的靶标。在RV 144临床试验中产生的V1 V2抗体与HIV感染风险降低相关，但这些抗体没有广泛的中和活性。靶向V1 V2的抗体也与用猿猴免疫缺陷病毒（SIV）或猿猴/人类免疫缺陷病毒（SHIV）攻击的免疫猕猴中的病毒载量降低相关。为了将免疫应答集中在V1 V2上，我们将天然的糖基化V1 V2结构域嫁接到五种不同的多聚体支架蛋白上，并在猕猴中进行比较免疫原性研究。接种疫苗的猕猴产生了高滴度的血浆和粘膜抗体，其靶向结构上不同的V1 V2表位。血浆抗体显示出有限的中和活性，但对ADCC和吞噬作用具有功能活性，这在免疫结束后1-2年可检测到。这项研究表明，多价的，糖基化的V1 V2-支架蛋白免疫原集中在V1 V2的抗体反应，并在诱导多功能抗体与保护相关的特性是不同的有效性。
The V1V2 region of the HIV-1 envelope is the target of several broadly neutralizing antibodies (bNAbs). Antibodies to V1V2 elicited in the RV144 clinical trial correlated with a reduced risk of HIV infection, but these antibodies were without broad neutralizing activity. Antibodies targeting V1V2 also correlated with a reduced viral load in immunized macaques challenged with simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV). To focus immune responses on V1V2, we engrafted the native, glycosylated V1V2 domain onto five different multimeric scaffold proteins and conducted comparative immunogenicity studies in macaques. Vaccinated macaques developed high titers of plasma and mucosal antibodies that targeted structurally distinct V1V2 epitopes. Plasma antibodies displayed limited neutralizing activity but were functionally active for ADCC and phagocytosis, which was detectable 1-2 years after immunizations ended. This study demonstrates that multivalent, glycosylated V1V2-scaffold protein immunogens focus the antibody response on V1V2 and are differentially effective at inducing polyfunctional antibodies with characteristics associated with protection.