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Early Establishment of -Herpesvirus Latency: Implications for Immune Control¹

Emilio Flaño^2,*, Qingmei Jia, John Moore^*, David L. Woodland^*, Ren Sun and Marcia A. Blackman^3,*

^* Trudeau Institute, Saranac Lake, NY 12983; and Department of Molecular and Medical Pharmacology, AIDS Institute, Jonsson Comprehensive Cancer Center, Dental Research Institute, and Molecular Biology Institute, University of California, Los Angeles, CA 90095

The human -herpesviruses, EBV and Kaposi’s sarcoma-associated herpesvirus, infect >90% of the population worldwide, and latent infection is associated with numerous malignancies. Rational vaccination and therapeutic strategies require an understanding of virus-host interactions during the initial asymptomatic infection. Primary EBV infection is associated with virus replication at epithelial sites and entry into the circulating B lymphocyte pool. The virus exploits the life cycle of the B cell and latency is maintained long term in resting memory B cells. In this study, using a murine -herpesvirus model, we demonstrate an early dominance of latent virus at the site of infection, with lung B cells harboring virus almost immediately after infection. These data reinforce the central role of the B cell not only in the later phase of infection, but early in the initial infection. Early inhibition of lytic replication does not impact the progression of the latent infection, and latency is established in lymphoid tissues following infection with a replication-deficient mutant virus. These data demonstrate that lytic viral replication is not a requirement for -herpesvirus latency in vivo and suggest that viral latency can be disseminated by cellular proliferation. These observations emphasize that prophylactic vaccination strategies must target latent -herpesvirus at the site of infection.

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