Thayer School of Engineering, Dartmouth College, Hanover, NH 03755.
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006.
Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2221247120. doi: 10.1073/pnas.2221247120. Epub 2023 May 8.
The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it remains unclear whether augmenting the effector functions elicited by broadly neutralizing antibodies (bNAbs) may also improve their clinical potential. Among these effector functions, complement-mediated activities, which can culminate in the lysis of virions or infected cells, have been the least well studied. Here, functionally modified variants of the second-generation bNAb 10-1074 with ablated and enhanced complement activation profiles were used to examine the role of complement-associated effector functions. When administered prophylactically against simian-HIV challenge in rhesus macaques, more bNAb was required to prevent plasma viremia when complement activity was eliminated. Conversely, less bNAb was required to protect animals from plasma viremia when complement activity was enhanced. These results suggest that complement-mediated effector functions contribute to in vivo antiviral activity, and that their engineering may contribute to the further improvements in the efficacy of antibody-mediated prevention strategies.
广谱中和抗体（bNAb）的首次临床疗效试验的效果不如预期，这表明需要改进以预防 HIV 感染。尽管已经投入了大量精力来优化中和的广度和效力，但仍不清楚增强广谱中和抗体（bNAbs）引起的效应功能是否也可以提高其临床潜力。在这些效应功能中，补体介导的活性（最终可导致病毒或感染细胞的裂解）研究得最少。在这里，使用功能修饰的第二代 bNAb 10-1074 的变体，这些变体具有被削弱和增强的补体激活特征，用于研究补体相关效应功能的作用。当在恒河猴中预防性给药以预防感染猴免疫缺陷病毒（simian-HIV）时，当消除补体活性时，需要更多的 bNAb 来预防血浆病毒血症。相反，当增强补体活性时，需要较少的 bNAb 来保护动物免受血浆病毒血症的侵害。这些结果表明，补体介导的效应功能有助于体内抗病毒活性，并且它们的工程化可能有助于进一步提高抗体介导的预防策略的功效。
