Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2022 Sep 6;13(1):5236. doi: 10.1038/s41467-022-32783-2.
SIVmac239 infection of macaques is a favored model of human HIV infection. However, the SIVmac239 envelope (Env) trimer structure, glycan occupancy, and the targets and ability of neutralizing antibodies (nAbs) to protect against SIVmac239 remain unknown. Here, we report the isolation of SIVmac239 nAbs that recognize a glycan hole and the V1/V4 loop. A high-resolution structure of a SIVmac239 Env trimer-nAb complex shows many similarities to HIV and SIVcpz Envs, but with distinct V4 features and an extended V1 loop. Moreover, SIVmac239 Env has a higher glycan shield density than HIV Env that may contribute to poor or delayed nAb responses in SIVmac239-infected macaques. Passive transfer of a nAb protects macaques from repeated intravenous SIVmac239 challenge at serum titers comparable to those described for protection of humans against HIV infection. Our results provide structural insights for vaccine design and shed light on antibody-mediated protection in the SIV model.
SIVmac239 感染恒河猴是人类 HIV 感染的首选模型。然而，SIVmac239 的包膜（Env）三聚体结构、聚糖占有率，以及中和抗体（nAbs）的靶标和保护能力针对 SIVmac239 仍不清楚。在这里，我们报告了分离 SIVmac239 nAbs 的研究，这些 nAbs 可识别聚糖孔和 V1/V4 环。SIVmac239 Env 三聚体-nAb 复合物的高分辨率结构与 HIV 和 SIVcpz Envs 非常相似，但 V4 特征和延伸的 V1 环不同。此外，SIVmac239 Env 的聚糖屏蔽密度高于 HIV Env，这可能导致 SIVmac239 感染的恒河猴中 nAb 反应不佳或延迟。nAb 的被动转移可保护猕猴免受重复静脉内 SIVmac239 攻击，血清滴度与描述的可预防人类 HIV 感染的水平相当。我们的研究结果为疫苗设计提供了结构见解，并阐明了 SIV 模型中的抗体介导的保护。
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