Date Published: December 27, 2012
Publisher: Public Library of Science
Author(s): Makoto Ohashi, Mark H. Fogg, Nina Orlova, Carol Quink, Fred Wang, Richard Longnecker.
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.
Acute Epstein-Barr virus (EBV) infection is the most common cause of Infectious Mononucleosis (IM). Once infected, EBV persists in rare peripheral blood lymphocytes for the life of the host . Almost all humans are persistently EBV infected by adulthood, and persistent EBV infection is almost always asymptomatic as long as host immunity is intact. The number of virus-infected peripheral blood lymphocytes, or virus setpoint, during persistent EBV infection is stable over time . However, in rare instances, persistent infection leads to EBV-associated cancers such as Hodgkin lymphoma, Burkitt lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and B cell lymphomas in immunocompromised people . How virus setpoints are established, how cancer develops from persistent EBV infection, and how virus setpoints affect cancer development remain important unanswered questions.
These experiments break new ground in two major areas by taking studies of EBV gene function into the context of a natural host and by exploring viral blockade of CSF-1 signaling, an immune evasion strategy not previously described for any other virus. Our studies indicate that viral amplification during acute EBV infection is susceptible to CSF-1-induced immune responses since mutating rhBARF1 resulted in blunting of acute viral load during the first 16 weeks after oral inoculation. In addition, we found a dramatic lowering of the virus setpoint during persistent infection when the virus was incapable of blocking CSF-1-induced immune responses. This anti-viral effect could be reversed by either immunosuppressing the host via SHIV infection or by restoring CSF-1 blocking ability to the rhBARF1 ORF.