Abstract
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. In this study, we demonstrate that infection of human primary naïve 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, without having a measurable effect on KSHV latency, AID impinges directly on the viral fitness by inhibiting lytic reactivation and reducing infectivity of KSHV virions. Importantly, we uncover two KSHV-encoded microRNAs that directly regulate AID abundance, further reinforcing the role for AID in the antiviral response. Together our findings reveal additional functions for AID in innate immune defense against KSHV with implications for a broader involvement in innate immunity to other pathogens.
Highlights
Herpesviruses have co-evolved with their hosts for millions of years, acquiring means to evade and manipulate host immune responses [1]
Activation-induced cytidine deaminase (AID) is defined as a factor required for a robust humoral immune response given its role in somatic hypermutation (SHM) and class-switch recombination (CSR)
Our study reveals an additional role for AID in innate immune defense against a human c-herpesvirus, Kaposi’s sarcoma-associated herpesvirus (KSHV)
Summary
Herpesviruses have co-evolved with their hosts for millions of years, acquiring means to evade and manipulate host immune responses [1] Evolutionary success of these viruses is highlighted by their life-long persistence, high prevalence and minimal pathological burden in immunocompetent hosts. Kaposi’s Sarcoma Associated Herpesvirus (KSHV) is a member of the human c-herpesvirus family characterized by lymphotropism and strict host specificity. It is the causative agent of Kaposi’s Sarcoma, the most common form of malignancy in AIDS patients, and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [2,3,4]. Upon entry into the lytic life cycle, virtually all viral genes (87 have been identified far) are activated in a temporal fashion, the viral genome is replicated and progeny virions are produced, generally resulting in death of the infected cell
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