Ayers Katelyn N, Lauver Matthew D, Alexander Kalynn M, Jin Ge, Paraiso Kitt, Ochetto Alyssa, Garg Sonal, Goetschius Daniel J, Hafenstein Susan L, Wang Joseph Che-Yen, Lukacher Aron E
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA 17033, USA.
Cellecta, Inc., Mountain View, CA 94043, USA.
bioRxiv. 2024 Dec 23:2024.12.22.629980. doi: 10.1101/2024.12.22.629980.
How changes in the quality of anti-viral antibody (Ab) responses due to pre-existing or acquired CD4 T cell insufficiency affect virus evolution during persistent infection are unknown. Using mouse polyomavirus (MuPyV), we found that CD4 T cell depletion before infection results in short-lived plasma cells secreting low-avidity antiviral IgG with limited BCR diversity and weak virus-neutralizing ability. CD4 T cell deficiency during persistent infection incurs a shift from a T-dependent (TD) to T-independent (TI) Ab response, resembling the pre-existing TI Ab response. CD4 T cell loss before infection or during persistent infection is conducive for emergence of Ab-escape variants. Cryo-EM reconstruction of complexes of MuPyV virions with polyclonal IgG directly from infected mice with pre-existing or acquired CD4 T cell deficiency enabled visualization of shortfalls in TI IgG binding. By debilitating the antiviral IgG response, CD4 T cell deficiency sets the stage for outgrowth of variant viruses resistant to neutralization.
由于预先存在或后天获得的CD4 T细胞功能不全导致的抗病毒抗体（Ab）反应质量变化如何影响持续性感染期间的病毒进化尚不清楚。利用小鼠多瘤病毒（MuPyV），我们发现感染前CD4 T细胞耗竭会导致分泌低亲和力抗病毒IgG的短命浆细胞，其BCR多样性有限且病毒中和能力较弱。持续性感染期间的CD4 T细胞缺陷会导致从T细胞依赖性（TD）抗体反应转变为T细胞非依赖性（TI）抗体反应，类似于预先存在的TI抗体反应。感染前或持续性感染期间CD4 T细胞的丧失有利于抗体逃逸变体的出现。通过对直接来自预先存在或后天获得CD4 T细胞缺陷的感染小鼠的MuPyV病毒粒子与多克隆IgG复合物进行冷冻电镜重建，能够观察到TI IgG结合的不足。通过削弱抗病毒IgG反应，CD4 T细胞缺陷为抗中和变异病毒的生长奠定了基础。
