title: An Epstein-Barr virus encoded inhibitor of Colony Stimulating Factor-1 signaling is an important determinant for acute and persistent EBV infection.
abstract: Acute Epstein-Barr virus (EBV) infection is the most common cause of Infectious Mononucleosis. Nearly all adult humans harbor life-long, persistent EBV infection which can lead to development of cancers including Hodgkin Lymphoma, Burkitt Lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and lymphomas in immunosuppressed patients. BARF1 is an EBV replication-associated, secreted protein that blocks Colony Stimulating Factor 1 (CSF-1) signaling, an innate immunity pathway not targeted by any other virus species. To evaluate effects of BARF1 in acute and persistent infection, we mutated the BARF1 homologue in the EBV-related herpesvirus, or lymphocryptovirus (LCV), naturally infecting rhesus macaques to create a recombinant rhLCV incapable of blocking CSF-1 (ΔrhBARF1). Rhesus macaques orally challenged with ΔrhBARF1 had decreased viral load indicating that CSF-1 is important for acute virus infection. Surprisingly, ΔrhBARF1 was also associated with dramatically lower virus setpoints during persistent infection. Normal acute viral load and normal viral setpoints during persistent rhLCV infection could be restored by Simian/Human Immunodeficiency Virus-induced immunosuppression prior to oral inoculation with ΔrhBARF1 or infection of immunocompetent animals with a recombinant rhLCV where the rhBARF1 was repaired. These results indicate that BARF1 blockade of CSF-1 signaling is an important immune evasion strategy for efficient acute EBV infection and a significant determinant for virus setpoint during persistent EBV infection.
authors.affiliation: Department of Medicine, Brigham & Women's Hospital and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohashi
authors.forename: Mark H
authors.initials: MH
authors.lastname: Fogg
authors.forename: Nina
authors.initials: N
authors.lastname: Orlova
authors.forename: Carol
authors.initials: C
authors.lastname: Quink
authors.forename: Fred
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D003673:Defective Viruses / Q000235:genetics / Q000472:pathogenicity; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D055786:Gene Knockout Techniques; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000378:metabolism; D007113:Immunity, Innate; D018143:Lymphocryptovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta / Q000378:metabolism / Q000821:virology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology; D019562:Viral Load / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C086495:BARF1 protein, Human herpesvirus 4; D014764:Viral Proteins; D016173:Macrophage Colony-Stimulating Factor