Function of the Gamma HV68 M2 Antigen

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): gamma-herpesviruses are associated with the development of lymphoproliferative disorders and lymphomas, particularly in immunosuppressed individuals. Importantly, a detailed understanding of how chronic virus infection is established and maintained may identify possible targets for interfering with viral persistence in the host. Unfortunately, the human ?-herpesviruses (EBV and KSHV) have very narrow host tropism, thus limiting detailed studies of host-pathogen interactions. MHV68 infection of mice provides a tractable small animal model system for characterizing the role of specific genes in viral pathogenesis and maintenance of chronic infection. We have previously shown that the MHV68 M2 latency-associated antigen plays a critical role in both the establishment of latency and reactivation of MHV68 from infected B cells. Furthermore, our recent studies have shown that M2 induces an IL-10 dependent proliferation and differentiation of primary murine B cells - reminiscent of EBV-driven differentiation of primary human B cells. M2 regulation of cellular IL-10 expression is particularly intriguing given that EBV encodes an IL-10 homolog whose function during virus infection has remained enigmatic. In addition, M2 can drive terminal differentiation of latently infected B cells to plasma cells, with concomitant reactivation of MHV68. Notably, plasma cell differentiation has also been linked to EBV and KSHV reactivation - indicating that virus regulation of plasma cell differentiation is likely a conserved strategy among gammaherpesviruses. Characterization of MHV68 M2 antigen function is expected to reveal cellular pathways that are manipulated by ?-herpesviruses to facilitate persistence and reactivation from B cells, and may ultimately identify targets for the development of anti-viral drugs. We propose the follow 3 specific aims: Aim 1. Pathogenesis of M2 mutants in vivo: (1.a) Investigate route- and dose-dependent phenotypes of M2 mutants; (1.b) Analysis of M2 mutant phenotypes in mice lacking an adaptive antibody response; and (1.c) Analysis of B cell lines immortalized with MHV68 harboring mutations in the M2 gene. Aim 2. Regulation of M2 expression: (2.a) Identification of cell types expressing M2 in vivo; (2.b) Map and characterize cis-elements regulating M2 gene expression during latency. Aim 3. M2 manipulation of B cell signaling pathways: (3.a) Characterize M2 modulation of B cell signaling pathways and cellular gene expression; (3.b) Identification of M2-interacting proteins; (3.c) Characterize M2 induction of IL-10 expression; and (3.d) Characterize M2-mediated events in plasma cell differentiation.