Ma Krystal M, Sutton Henry J, Pratap Payal P, Steichen Jon M, Carnathan Diane, Quinn James, Kalyuzhniy Oleksandr, Liguori Alessia, Agrawal Sashank, Baboo Sabyasachi, Madden Patrick, Cottrell Christopher A, Willis Jordan R, Lee Jeong-Hyun, Landais Elise, Hu Xiaozhen, Ramezani-Rad Parham, Ozorowski Gabriel, Lewis Vanessa R, Diedrich Jolene K, Zhou Xiaoya, Altheide Tasha K, Phelps Nicole, Georgeson Erik, Alavi Nushin B, Lu Danny, Eskandarzadeh Saman, Kubitz Michael, Adachi Yumiko, Mullen Tina-Marie, Silva Murillo, Melo Mariane B, Himansu Sunny, Irvine Darrell J, Burton Dennis R, Yates John R, Paulson James C, Sok Devin, Wilson Ian A, Silvestri Guido, Ward Andrew B, Crotty Shane, Schief William R
Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.
IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.
Sci Immunol. 2025 Aug 22;10(110):eadt6660. doi: 10.1126/sciimmunol.adt6660.
An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb-related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo-electron microscopy revealed that elicited Apex bnAb-related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.
一种有效的预防性HIV疫苗可能需要诱导产生广泛中和抗体（bnAbs）。针对HIV包膜糖蛋白（Env）顶端区域的bnAbs是疫苗接种的有前景的靶点，因为与其他bnAbs相比，它们的体细胞超突变相对较少。大多数顶端bnAbs利用包含特定结合基序的异常长的重链互补决定区3（HCDR3）与Env结合，这降低了bnAb前体频率，并使得引发罕见的bnAb前体可能成为诱导顶端bnAb途径中的一个限制步骤。我们发现，用ApexGT6（一种经工程改造以结合顶端bnAb前体的Env三聚体）对恒河猴进行佐剂化蛋白或mRNA脂质纳米颗粒（LNP）免疫，能持续诱导出具有长HCDR3且带有bnAb样序列基序的顶端bnAb相关前体。冷冻电子显微镜显示，引发的顶端bnAb相关HCDR3具有结合了几种原型顶端bnAbs元件的结构。这些结果在远交灵长类动物中实现了HIV疫苗开发的一个关键里程碑。
