Host immune responses to a viral immune modulating protein: immunogenicity of viral interleukin-10 in rhesus cytomegalovirus-infected rhesus macaques.
BACKGROUND
Considerable evidence has accumulated that multiple viruses, bacteria, and protozoa manipulate interleukin-10 (IL-10)-mediated signaling through the IL-10 receptor (IL-10R) in ways that could enable establishment of a persistent microbial infection. This suggests that inhibition of pathogen targeting of IL-10/IL-10R signaling could prevent microbial persistence. Human cytomegalovirus (HCMV) and rhesus cytomegalovirus (RhCMV) express a viral interleukin-10 (cmvIL-10 and rhcmvIL-10, respectively) with comparable immune modulating properties in vitro to that of their host's cellular IL-10 (cIL-10). A prior study noted that rhcmvIL-10 alters innate and adaptive immunity to RhCMV in vivo, consistent with a central role for rhcmvIL-10 during acute virus-host interactions. Since cmvIL-10 and rhcmvIL-10 are extremely divergent from the cIL-10 of their respective hosts, vaccine-mediated neutralization of their function could inhibit establishment of viral persistence without inhibition of cIL-10.


RESULTS
As a prelude to evaluating cmvIL-10-based vaccines in humans, the rhesus macaque model of HCMV was used to interrogate peripheral and mucosal immune responses to rhcmvIL-10 in RhCMV-infected animals. ELISA were used to detect rhcmvIL-10-binding antibodies in plasma and saliva, and an IL-12-based bioassay was used to quantify plasma antibodies that neutralized rhcmvIL-10 function. rhcmvIL-10 is highly immunogenic during RhCMV infection, stimulating high avidity rhcmvIL-10-binding antibodies in the plasma of all infected animals. Most infected animals also exhibited plasma antibodies that partially neutralized rhcmvIL-10 function but did not cross-neutralize the function of rhesus cIL-10. Notably, minimally detectable rhcmvIL-10-binding antibodies were detected in saliva.


CONCLUSIONS
This study demonstrates that rhcmvIL-10, as a surrogate for cmvIL-10, is a viable vaccine candidate because (1) it is highly immunogenic during natural RhCMV infection, and (2) neutralizing antibodies to rhcmvIL-10 do not cross-react with rhesus cIL-10. Exceedingly low rhcmvIL-10 antibodies in saliva further suggest that the oral mucosa, which is critical in RhCMV natural history, is associated with suboptimal anti-rhcmvIL-10 antibody responses.
Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
Meghan K
MK
Eberhardt
W L William
WL
Chang
Naomi J
NJ
Logsdon
Yujuan
Y
Yue
Mark R
MR
Walter
Peter A
PA
Barry
D000818:Animals; D057134:Antibodies, Neutralizing / Q000032:analysis / Q000097:blood / Q000276:immunology; D000917:Antibody Formation; D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014764:Viral Proteins / Q000276:immunology*
D057134:Antibodies, Neutralizing; D014764:Viral Proteins; D016753:Interleukin-10