The CD4 T cell-independent IgG response during persistent virus infection favors emergence of neutralization-escape variants
Ayers, K. N.; Lauver, M. D.; Alexander, K. M.; Jin, G.; Paraiso, K.; Ochetto, A.; Garg, S.; Goetschius, D. J.; Hafenstein, S. L.; Wang, J. C.-Y.; Lukacher, A. E.
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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. ONE SENTENCE SUMMARYPre-existing and acquired CD4 T cell deficiency facilitates outgrowth of Ab-escape viral variants during persistent infection.
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