Yates Nicole L, deCamp Allan C, Korber Bette T, Liao Hua-Xin, Irene Carmela, Pinter Abraham, Peacock James, Harris Linda J, Sawant Sheetal, Hraber Peter, Shen Xiaoying, Rerks-Ngarm Supachai, Pitisuttithum Punnee, Nitayapan Sorachai, Berman Phillip W, Robb Merlin L, Pantaleo Giuseppe, Zolla-Pazner Susan, Haynes Barton F, Alam S Munir, Montefiori David C, Tomaras Georgia D
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
J Virol. 2018 Mar 28;92(8). doi: 10.1128/JVI.01843-17. Print 2018 Apr 15.
Induction of broadly cross-reactive antiviral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier 2 neutralization phenotype. Unique antigenicity was determined by nonredundancy (Spearman correlation), and antigens were clustered using partitioning around medoids (PAM) to identify antigen diversity. Cross-validation demonstrated that the PAM method was better than selection by reactivity and random selection. Analysis of vaccine-elicited V1V2 binding antibody in longitudinal samples from the RV144 clinical trial revealed the striking heterogeneity among individual vaccinees in maintaining durable responses. These data support the idea that a major goal for vaccine development is to improve antibody levels, breadth, and durability at the population level. Elucidating the level and durability of vaccine-elicited binding antibody breadth needed for protection is critical for the development of a globally efficacious HIV vaccine. The path toward an efficacious HIV-1 vaccine will require characterization of vaccine-induced immunity that can recognize and target the highly genetically diverse virus envelope glycoproteins. Antibodies that target the envelope glycoproteins, including diverse sequences within the first and second hypervariable regions (V1V2) of gp120, were identified as correlates of risk for the one partially efficacious HIV-1 vaccine. To build upon this discovery, we experimentally and computationally evaluated humoral responses to define envelope glycoproteins representative of the antigenic diversity of HIV globally. These diverse envelope antigens distinguished binding antibody breadth and durability among vaccine candidates, thus providing insights for advancing the most promising HIV-1 vaccine candidates.
诱导具有靶向全球多样循环毒株能力的广泛交叉反应性抗病毒体液免疫反应是HIV-1免疫原设计的关键目标。该领域的一个主要差距是鉴定不同的HIV-1包膜抗原，以评估疫苗方案的结合抗体广度。在本研究中，我们定义了独特的抗原组来绘制HIV-1疫苗诱导的抗体广度和持久性。基于遗传和地理多样性选择了不同的HIV-1包膜糖蛋白，以涵盖全球流行情况，重点关注具有2级中和表型的性传播/奠基者病毒。通过非冗余性（斯皮尔曼相关性）确定独特的抗原性，并使用围绕中心点的划分（PAM）对抗原进行聚类以识别抗原多样性。交叉验证表明，PAM方法优于基于反应性的选择和随机选择。对RV144临床试验纵向样本中疫苗诱导的V1V2结合抗体的分析揭示了个体疫苗接种者在维持持久反应方面存在显著异质性。这些数据支持这样一种观点，即疫苗开发的一个主要目标是在人群水平上提高抗体水平、广度和持久性。阐明保护所需的疫苗诱导结合抗体广度的水平和持久性对于开发全球有效的HIV疫苗至关重要。通往有效HIV-1疫苗的道路将需要对能够识别和靶向高度基因多样化的病毒包膜糖蛋白的疫苗诱导免疫进行表征。靶向包膜糖蛋白的抗体，包括gp120第一和第二高变区（V1V2）内的不同序列，被确定为一种部分有效的HIV-1疫苗的风险相关因素。为了在此发现的基础上进一步研究，我们通过实验和计算评估体液免疫反应，以确定代表全球HIV抗原多样性的包膜糖蛋白。这些不同的包膜抗原区分了候选疫苗之间的结合抗体广度和持久性，从而为推进最有前景的HIV-1候选疫苗提供了见解。
