A secreted chemokine binding protein encoded by murine gammaherpesvirus-68is necessary for the establishment of a normal latent load

Herpesviruses encode a variety of proteins with the potential to disrupt ch emokine signaling, and hence immune organization. However, little is known of how these might function in vivo. The B cell-tropic murine gammaherpesvi rus-68 (MHV-68) is related to the Kaposi's sarcorna-associated herpesvirus (KSHV), but whereas KSHV expresses small chemokine homologues, MHV-68 encod es a broad spectrum chemokine binding protein (M3). Here we have analyzed t he effect on viral pathogenesis of a targeted disruption of the M3 gene. Af ter intranasal infection, an M3 deficiency had surprisingly little effect o n lytic cycle replication in the respiratory tract or the initial spread of virus to lymphoid tissues. However, the amplification of latently infected B cells in the spleen that normally drives MHV-68-induced infectious niono nucleosis failed to occur. Thus, there was a marked reduction in latent vir us recoverable by in vitro reactivation, latency-associated viral tRNA tran scripts detectable by in situ hybridization, total viral DNA load, and viru s-driven B cell activation. In vivo CD8(+) T cell depletion largely reverse d this deficiency, suggesting that the chemokine neutralization afforded by M3 may function to block effective CD8(+) T cell recruitment into lymphoid tissue during the expansion of latently infected B cell numbers. In the ab sence of M3, MHV-68 was unable to establish a normal latent load.