Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
J Virol. 2021 Jan 13;95(3). doi: 10.1128/JVI.01667-20.
Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term human immunodeficiency virus (HIV) remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth, as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the abilities of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and nonneutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain dependent. Moreover, we observe a strong correlation between the neutralization potencies and nonneutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in future passive immunization studies using the SHIV challenge model.
每日抗逆转录病毒治疗(ART)的负担和临床毒性强调了需要替代策略,以在停止 ART 后诱导长期的人类免疫缺陷病毒(HIV)缓解。广泛中和抗体(bNAbs)既能中和游离病毒粒子,又能介导针对感染细胞的效应功能,因此代表了一种主要的免疫治疗方法。为了提高效力和广度,并限制耐药病毒株的发展,很可能需要联合使用 bNAbs。因此,关键是要确定能够针对大量 HIV 株实现强大的多功能抗病毒活性的 bNAb 组合。在这项研究中,我们系统地评估了单个 bNAb 和三 bNAb 组合介导针对大量跨群恒河猴 - 人免疫缺陷病毒(SHIV)的强大多功能抗病毒活性的能力,这些病毒通常被用作在非人类灵长类动物模型中针对 HIV 包膜的治疗策略验证的工具。我们证明,大多数 bNAb 能够针对跨群 SHIV 介导中和和非中和效应功能,尽管对 V3 聚糖特异性 bNAb 的敏感性高度依赖于株。此外,我们观察到 bNAb 对传播/原始 SHIV CH505 的中和效力和非中和效应功能之间存在很强的相关性。最后,我们确定了几种包含 CD4 结合位点、V2 聚糖和 gp120-gp41 界面靶向 bNAb 的三 bNAb 组合,这些组合能够针对多个 A、B、C 和 D 群 SHIV 介导协同的多功能抗病毒活性。最佳的 bNAb 免疫疗法将需要针对广泛的 HIV 株介导多种抗病毒功能。我们对 SHIV 进行的三 bNAb 组合的系统评估将确定具有协同、多功能抗病毒活性的 bNAb,这将为选择最佳组合设计的候选 bNAb 提供信息。所鉴定的组合可以在使用 SHIV 挑战模型的未来被动免疫研究中进行验证。