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Exploitation of IL-10 Signaling Pathways: The Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection.

Exploitation of IL-10 Signaling Pathways: The Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection.
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Eberhardt MK, Deshpande A, Fike J, Short R, Schmidt KA, Blozis SA, Walter MR, Barry PA,


Eberhardt MK, Deshpande A, Fike J, Short R, Schmidt KA, Blozis SA, Walter MR, Barry PA, (click to view)

Eberhardt MK, Deshpande A, Fike J, Short R, Schmidt KA, Blozis SA, Walter MR, Barry PA,

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Journal of virology 2016 8 24() pii

Abstract

There is accumulating evidence that the viral interleukin-10 (vIL-10) ortholog of both human and rhesus cytomegalovirus (HCMV and RhCMV, respectively) suppresses the functionality of cell types that would be critical to contain virus dissemination and help shape long-term immunity during the earliest virus-host interactions. In particular, exposure of macrophages, peripheral blood mononuclear cells, monocyte-derived dendritic cells, and plasmacytoid dendritic cells to vIL-10 suppresses multiple effector functions, including notably, those that link innate and adaptive immune responses. Further, vaccination of RhCMV-uninfected rhesus macaques with non-functional forms of RhCMV vIL-10 greatly restricts parameters of RhCMV infection following RhCMV challenge of the vaccines. Vaccinees exhibited significantly reduced shedding of RhCMV in saliva and urine following RhCMV challenge compared to unvaccinated controls. Based on the evidence that vIL-10 is critical during acute infection, the role of vIL-10 during persistent infection was analyzed in rhesus macaques infected long-term with RhCMV to determine whether post-infection vaccination against vIL-10 could change the virus-host balance. RhCMV-seropositive macaques, which were shedding RhCMV in saliva, were vaccinated with non-functional RhCMV vIL-10, and shedding levels of RhCMV in saliva were evaluated. Following robust increases in vIL-10-binding and vIL-10-neutralizing antibodies, shedding levels of RhCMV modestly declined, consistent with the interpretation that vIL-10 may play a functional role during persistent infection. However, a more significant association was observed between the levels of cellular IL-10 secreted in PBMC exposed to RhCMV antigens and shedding of RhCMV in saliva. This result implies that RhCMV persistence is associated with the induction of cIL-10 receptor-mediated signaling pathways.

IMPORTANCE
Human health is adversely impacted by viruses that establish lifelong infections that are often accompanied with increased morbidity and mortality (e.g., HIV, hepatitis C virus, human cytomegalovirus). A longstanding but unfulfilled goal has been to develop post-infection vaccine strategies that could ‘reboot’ the immune system of an infected individual in ways that enable the infected host to develop immune responses that clear reservoirs of persistent virus infection, effectively curing the host of infection. This concept was evaluated in rhesus macaques infected long-term with rhesus cytomegalovirus by repeatedly immunizing infected animals with non-functional versions of the rhesus cytomegalovirus-encoded, viral interleukin-10 immune modulating protein. Following vaccine-mediated boosting of antibody titers to viral interleukin-10, there was modest evidence for increased immunological control of the virus following vaccination. More significantly, data were also obtained indicating that rhesus cytomegalovirus is able to persist due to upregulation of the cellular interleukin-10 signaling pathway.

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