Richel Elie, Cordsmeier Arne, Bauer Larissa, Fraedrich Kirsten, Vestweber Ramona, Roshani Berit, Stolte-Leeb Nicole, Ensser Armin, Stahl-Hennig Christiane, Überla Klaus
University Hospital Erlangen, Institute of Clinical and Molecular Virology, Friedrich-Alexander Universität Erlangen-Nürnberg, Germany.
German Primate Center, Göttingen, Germany.
PLoS Pathog. 2024 Dec 26;20(12):e1012777. doi: 10.1371/journal.ppat.1012777. eCollection 2024 Dec.
Broadly neutralizing antibodies (bnAbs) against HIV-1 have been shown to protect from systemic infection. When employing a novel challenge virus that uses HIV-1 Env for entry into target cells during the first replication cycle, but then switches to SIV Env usage, we demonstrated that bnAbs also prevented mucosal infection of the first cells. However, it remained unclear whether antibody Fc-effector functions contribute to this sterilizing immunity. Therefore, additional challenge viruses were produced that contain SIV Env and graded doses of a fusion-defective trimer of HIV-1 Env, to which the bnAb, PGT121 can bind without interfering with the SIV Env-based cell entry. After administration of either PGT121 or its mutant deficient in Fc-effector functions, rhesus macaques were intrarectally exposed to these challenge viruses and to those using either HIV-1 Env or SIV Env for entry into the first cells. Both antibodies similarly reduced infection events with the challenge virus using HIV-1 Env by a factor close to 200. Incorporating fusion-defective HIV-1 Env trimers into the particles of the challenge viruses at densities observed in primary virus isolates did not reduce SIV Env-mediated infection events. The results indicate that the sparsity of bnAb binding-sites on HIV-1 virions limits the contribution of Fc-effector functions to provide sterilizing immunity against mucosal viral infection. Hence, harnessing Fc-effector functions for sterilizing immunity against mucosal HIV-1 infection may require strategies to increase the degree of antibody opsonization.
已证明针对HIV-1的广泛中和抗体（bnAbs）可预防全身感染。当使用一种新型攻击病毒时，该病毒在第一个复制周期利用HIV-1包膜进入靶细胞，但随后切换为使用SIV包膜，我们证明bnAbs也可预防首个细胞的黏膜感染。然而，尚不清楚抗体的Fc效应功能是否有助于这种无菌免疫。因此，制备了另外的攻击病毒，其含有SIV包膜和分级剂量的HIV-1包膜融合缺陷三聚体，bnAb PGT121可与其结合而不干扰基于SIV包膜的细胞进入。给予PGT121或其Fc效应功能缺陷的突变体后，将恒河猴经直肠暴露于这些攻击病毒以及那些使用HIV-1包膜或SIV包膜进入首个细胞的病毒。两种抗体同样将使用HIV-1包膜的攻击病毒的感染事件减少了近200倍。以在原始病毒分离株中观察到的密度将融合缺陷的HIV-1包膜三聚体掺入攻击病毒颗粒中，并未减少SIV包膜介导的感染事件。结果表明，HIV-1病毒粒子上bnAb结合位点的稀疏性限制了Fc效应功能对提供针对黏膜病毒感染的无菌免疫的贡献。因此，利用Fc效应功能实现针对黏膜HIV-1感染的无菌免疫可能需要增加抗体调理作用程度的策略。
