This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gammaherpesviruses are etiologically associated with lymphomas. Murine gammaherpesvirus 68 (gHV68) infects rodents and shares many genetic and biologic properties with the human gammaherpesviruses, Epstein Barr virus (EBV) and Kaposi?s sarcoma-associated herpesvirus (KSHV). A critical determinant in chronic infection by gammaherpesviruses is their ability to establish latency in a lymphocyte reservoir. gHV68 is an ideal model system since the virus is easily propagated in culture and mouse infections recapitulate many aspects of human infection with EBV. NF-kappa B is a family of transcription factors that are key players in B cell maturation, survival, activation, and differentiation. To date, all gammaherpesviruses encode viral modulators of NF-kB signaling that play critical roles in promoting cell survival and proliferation. However, the role of NF-kB signaling in the establishment of latency in vivo has not been previously addressed. To this end, we generated a recombinant gHV68 virus that expressed a constitutively active form of the inhibitor of NF-kB, IkBaM. We found that inhibition of NF-kB signaling upon infection with gHV68-IkBaM had no impact during lytic replication in cell culture or in the lung epithelium after intranasal infection. However, there was a substantial decrease in the frequency of latently-infected lymphocytes in the lung (90% reduction) and spleens (97% reduction) sixteen days after intranasal infection. This phenotype was not rescued by the constitutive expression of the pro-survival molecule bcl-2 upon infection of transgenic mice that express bcl-2 in B cells. While the immune response to the virus was not substantially altered in mice infected with gHV68-IkBaM, there was an association of decreased latent viral load with a loss of activated, CD69+ B cells. We conclude that NF-kB signaling is likely critical at multiple stages of gHV68 pathogenesis and provides a target for therapeutic intervention in gammaherpesvirus persistence in the host.
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