Karlsson Ingrid, Borggren Marie, Jensen Sanne Skov, Heyndrickx Leo, Stewart-Jones Guillaume, Scarlatti Gabriella, Fomsgaard Anders
1 Department of Virology and Special Microbial Diagnostic, Statens Serum Institut , Copenhagen, Denmark .
2 Infectious Disease Research Unit, Clinical Institute, University of Southern Denmark , Odense, Denmark .
AIDS Res Hum Retroviruses. 2018 Feb;34(2):206-217. doi: 10.1089/AID.2017.0140. Epub 2017 Nov 17.
The induction of both neutralizing antibodies and non-neutralizing antibodies with effector functions, for example, antibody-dependent cellular cytotoxicity (ADCC), is desired in the search for effective vaccines against HIV-1. In the pursuit of novel immunogens capable of inducing an efficient antibody response, rabbits were immunized with selected antigens using different prime-boost strategies. We immunized 35 different groups of rabbits with Env antigens from clinical HIV-1 subtypes A and B, including immunization with DNA alone, protein alone, and DNA prime with protein boost. The rabbit sera were screened for ADCC activity using a GranToxiLux-based assay with human peripheral blood mononuclear cells as effector cells and CEM.NKR cells coated with HIV-1 envelope as target cells. The groups with the highest ADCC activity were further characterized for cross-reactivity between HIV-1 subtypes. The immunogen inducing the most potent and broadest ADCC response was a trimeric gp140. The ADCC activity was highest against the HIV-1 subtype corresponding to the immunogen. The ADCC activity did not necessarily reflect neutralizing activity in the pseudovirus-TZMbl assay, but there was an overall correlation between the two antiviral activities. We present a rabbit vaccination model and an assay suitable for screening HIV-1 vaccine candidates for the induction of ADCC-mediating antibodies in addition to neutralizing antibodies. The antigens and/or immunization strategies capable of inducing antibodies with ADCC activity did not necessarily induce neutralizing activity and vice versa. Nevertheless, we identified vaccine candidates that were able to concurrently induce both types of responses and that had ADCC activity that was cross-reactive between different subtypes. When searching for an effective vaccine candidate, it is important to evaluate the antibody response using a model and an assay measuring the desired function.
在寻找抗HIV-1有效疫苗的过程中，人们期望诱导出具有效应功能的中和抗体和非中和抗体，例如抗体依赖性细胞毒性（ADCC）。为了寻找能够诱导有效抗体反应的新型免疫原，我们使用不同的初免-加强策略，用选定的抗原免疫兔子。我们用来自临床HIV-1 A和B亚型的Env抗原免疫了35组不同的兔子，包括单独使用DNA免疫、单独使用蛋白质免疫以及DNA初免-蛋白质加强免疫。使用基于GranToxiLux的检测方法，以人外周血单个核细胞作为效应细胞，以包被有HIV-1包膜的CEM.NKR细胞作为靶细胞，筛选兔血清中的ADCC活性。对ADCC活性最高的组进一步分析HIV-1亚型之间的交叉反应性。诱导最强且最广泛ADCC反应的免疫原是三聚体gp140。针对与免疫原对应的HIV-1亚型，ADCC活性最高。ADCC活性不一定反映假病毒-TZMbl检测中的中和活性，但这两种抗病毒活性之间总体存在相关性。我们提出了一种兔疫苗接种模型和一种检测方法，适用于筛选HIV-1疫苗候选物，以诱导除中和抗体外的ADCC介导抗体。能够诱导具有ADCC活性抗体的抗原和/或免疫策略不一定能诱导中和活性，反之亦然。然而，我们鉴定出了能够同时诱导两种反应类型且具有不同亚型间交叉反应性ADCC活性的疫苗候选物。在寻找有效的疫苗候选物时，使用能够测量所需功能的模型和检测方法评估抗体反应非常重要。
