A secreted chemokine binding protein encoded by murine gammaherpesvirus-68 is necessary for the establishment of a normal latent load.
Herpesviruses encode a variety of proteins with the potential to disrupt chemokine signaling, and hence immune organization. However, little is known of how these might function in vivo. The B cell-tropic murine gammaherpesvirus-68 (MHV-68) is related to the Kaposi's sarcoma-associated herpesvirus (KSHV), but whereas KSHV expresses small chemokine homologues, MHV-68 encodes a broad spectrum chemokine binding protein (M3). Here we have analyzed the effect on viral pathogenesis of a targeted disruption of the M3 gene. After intranasal infection, an M3 deficiency had surprisingly little effect on 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 mononucleosis failed to occur. Thus, there was a marked reduction in latent virus recoverable by in vitro reactivation, latency-associated viral tRNA transcripts detectable by in situ hybridization, total viral DNA load, and virus-driven B cell activation. In vivo CD8(+) T cell depletion largely reversed 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 absence of M3, MHV-68 was unable to establish a normal latent load.
Bridgeman
A
A
Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
Stevenson
P G
PG
Simas
J P
JP
Efstathiou
S
S
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D018142:Gammaherpesvirinae / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D018390:Gene Targeting; D006566:Herpesviridae Infections / Q000209:etiology / Q000276:immunology / Q000821:virology; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D012343:RNA, Transfer / Q000032:analysis / Q000235:genetics; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D017931:DNA Primers; C118862:M3 protein, Murine gammaherpesvirus; D012367:RNA, Viral; D014764:Viral Proteins; D012343:RNA, Transfer