Ahmed Shamim, Parthasarathy Durgadevi, Newhall Rachael, Picard Tashina, Aback Morgainne, Ratnapriya Sneha, Arndt William, Vega-Rodriguez Widaliz, Kirk Natalie M, Liang Yuying, Herschhorn Alon
Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA.
School of Dentistry, University of Minnesota, Minneapolis, MN, 55455, USA.
NPJ Vaccines. 2023 Nov 24;8(1):181. doi: 10.1038/s41541-023-00774-z.
An effective human immunodeficiency virus type I (HIV-1) vaccine that robustly elicits broadly neutralizing antibodies (bnAbs) against HIV-1 envelope glycoproteins (Envs) to block viral entry is still not available. Thus, identifying triggers for elicitation of different types of anti-HIV-1 Env antibodies by vaccination could provide further guidance for immunogen design and vaccine development. Here, we studied the immune response to HIV-1 Env immunogens in rabbits. We show that sequential immunizations with conformation-specific Env immunogens can elicit low titer but broad neutralization responses against heterologous, neutralization-resistant (tier 2/3) transmitted/founder (T/F) HIV-1 strains. More importantly, an mRNA vaccine candidate that could mediate the presentation of a cytoplasmic tail-deleted (ΔCT) HIV-1 Env immunogen on virus-like particles significantly increased the neutralization response. This strategy shifted the type of elicited antibodies, decreasing the level of binding to soluble Envs while significantly increasing their overall viral neutralization activity. The breadth and potency of neutralizing response against heterologous, T/F HIV-1 strains significantly increased in a subset of rabbits. Efficient neutralization activity was associated with high cellular immune responses specific to HIV-1 Envs. These results help to understand the immune response to different immunization schemes and will allow developing new approaches to selectively manipulate the type of humoral immune response by specific vaccination.
目前仍没有一种有效的I型人类免疫缺陷病毒（HIV-1）疫苗，能够强有力地诱导产生针对HIV-1包膜糖蛋白（Env）的广泛中和抗体（bnAbs）以阻断病毒进入。因此，确定通过疫苗接种引发不同类型抗HIV-1 Env抗体的触发因素可为免疫原设计和疫苗开发提供进一步指导。在此，我们研究了家兔对HIV-1 Env免疫原的免疫反应。我们发现，用构象特异性Env免疫原进行序贯免疫可引发低滴度但针对异源、中和抗性（2/3层）传播/奠基者（T/F）HIV-1毒株的广泛中和反应。更重要的是，一种能够介导在病毒样颗粒上呈递缺失细胞质尾（ΔCT）的HIV-1 Env免疫原的mRNA候选疫苗显著增强了中和反应。这种策略改变了所诱导抗体的类型，降低了与可溶性Env的结合水平，同时显著提高了其整体病毒中和活性。在一部分家兔中，针对异源T/F HIV-1毒株的中和反应的广度和效力显著增加。高效的中和活性与针对HIV-1 Env的高细胞免疫反应相关。这些结果有助于理解对不同免疫方案的免疫反应，并将有助于开发新方法，通过特定疫苗接种选择性地调控体液免疫反应的类型。
