The role of AID protein in the host response to viral infection

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DESCRIPTION (provided by applicant): AID is a cytidine deaminase necessary for somatic hypermutation and class switch recombination of immunoglobulin genes. In addition to this role in mediating antibody diversification within the vertebrate adaptive immune system, we have recently shown that AID also mediates a form of host response against viral infection. We have found that AID is specifically induced in primary B cells in response to viral infection by a transforming retrovirus (Abl-MLV). As a result of AID induction the proliferation of infected host cells is significantly restricted. This is true both in tissue culture infections as well as in vivo: we found that AID-deficient Abelson tumours are far more aggressive than their wildtype counterparts, when transplanted into wildtype recipients. These experiments describe a novel phenomenon with important implications for the host antiviral response both in vitro and in vivo. This proposal aims to investigate the molecular mechanism underlying this novel response to viral infection. Specifically, we propose to: a) Determine the mechanism by which AID restricts the proliferation of virally infected cells. We will first determine the residues of AID that are important in the host antiviral response. If catalytic activity is required, we will investigate various types of events downstream a cytidine deaminase lesion which could result in loss of proliferation in the host. If catalytic activity is not required we will investigate whether the ability of AID to bind nucleic acid, which is distinct from the ability to catalyze the reaction, is necessary for the phenotype. b) Understand how virally-induced AID is regulated. We will catalog the types of viruses for which AID induction is part of the host antiviral response, determine the types of cells for which this is an active anti-viral response and identify the pathways which lead to AID upregulation in the host cell. Together, these experiments will delineate the mechanism of action of this novel host response to viral infection and in addition, they will determine the signaling pathways which lead to this response.