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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.
Highlights
Acute Epstein-Barr virus (EBV) infection is the most common cause of Infectious Mononucleosis (IM)
To investigate how EBV interacts with the host to successfully establish acute and persistent infection, we combined the power of the rhesus macaque animal model for EBV infection with genetic engineering of the EBV-related herpesvirus, or lymphocryptovirus (LCV), that naturally infects rhesus macaques
In order to test the importance of rhBARF1-mediated Colony Stimulating Factor-1 (CSF-1) blockade in acute and persistent rhLCV infection, three rhLCVnaıve rhesus macaques were orally inoculated with 106 transforming units (TU) of a recombinant rhLCV (DrhBARF1) carrying a truncated rhBARF1 previously shown to be incapable of blocking CSF-1-mediated signaling [20]
Summary
Acute Epstein-Barr virus (EBV) infection is the most common cause of Infectious Mononucleosis (IM). EBV persists in rare peripheral blood lymphocytes for the life of the host [1]. 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 [2]. 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 [1]. How virus setpoints are established, how cancer develops from persistent EBV infection, and how virus setpoints affect cancer development remain important unanswered questions
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