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A role for host activation-induced cytidine deaminase in innate immune defense against herpesviruses


Activation-induced cytidine deaminase (AID) is specifically induced in germinal center B cells to carry out somatic hypermutation and class-switch recombination, two processes responsible for antibody diversification. Because of its mutagenic potential, AID expression and activity are tightly regulated to minimize unwanted DNA damage. Surprisingly, AID expression has been observed ectopically during pathogenic infections. However, the function of AID outside of the germinal centers remains largely uncharacterized. This dissertation demonstrates that infection of human primary naive B cells with Kaposi's sarcoma-associated herpesvirus (KSHV) rapidly induces AID expression in a cell intrinsic manner. We find that infected cells are marked for elimination by Natural Killer cells through upregulation of NKG2D ligands via the DNA-damage pathway, a pathway triggered by AID. Moreover, AID impinges directly on the viral fitness by inhibiting lytic reactivation without having a measurable effect on KSHV latency. We extend this analysis to the murine homologue of KSHV, MHV68 and find that AID mutates the viral genome at a rate that exceeds normal somatic mutation by several orders of magnitude. The tremendous mutational load accumulated by sequential passaging of MHV68 through AID-expressing cells leads to the eventual inactivation of the virus. Importantly, we uncover two KSHV-encoded microRNAs that directly regulate AID abundance, further reinforcing the value of AID in the antiviral response. Together our findings reveal an additional role for AID in innate immune defense against herpesviruses with implications for a broader role in innate immunity to other pathogens.

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