Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus

Naomi J. Logsdon, Meghan K. Eberhardt, Christopher E. Allen, Peter A Barry, Mark R. Walter

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Human cytomegalovirus (HCMV) expresses a viral ortholog (CMVIL-10) of human cellular interleukin-10 (cIL-10). Despite only ~26% amino acid sequence identity, CMVIL-10 exhibits comparable immunosuppressive activity with cIL-10, attenuates HCMV antiviral immune responses, and contributes to lifelong persistence within infected hosts. The low sequence identity between CMVIL-10 and cIL-10 suggests vaccination with CMVIL-10 may generate antibodies that specifically neutralize CMVIL-10 biological activity, but not the cellular cytokine, cIL-10. However, immunization with functional CMVIL-10 might be detrimental to the host because of its immunosuppressive properties. Methods and Findings: Structural biology was used to engineer biologically inactive mutants of CMVIL-10 that would, upon vaccination, elicit a potent immune response to the wild-type viral cytokine. To test the designed proteins, the mutations were incorporated into the rhesus cytomegalovirus (RhCMV) ortholog of CMVIL-10 (RhCMVIL-10) and used to vaccinate RhCMV-infected rhesus macaques. Immunization with the inactive RhCMVIL-10 mutants stimulated antibodies against wild-type RhCMVIL-10 that neutralized its biological activity, but did not cross-react with rhesus cellular IL-10. Conclusion: This study demonstrates an immunization strategy to neutralize RhCMVIL-10 biological activity using non-functional RhCMVIL-10 antigens. The results provide the methodology for targeting CMVIL-10 in vaccine, and therapeutic strategies, to nullify HCMV's ability to (1) skew innate and adaptive immunity, (2) disseminate from the site of primary mucosal infection, and (3) establish a lifelong persistent infection.

Original languageEnglish (US)
Article numbere28127
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 21 2011

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Human herpesvirus 5
Cytomegalovirus
interleukin-10
Interleukin-10
Immunization
Vaccines
vaccines
mutants
Bioactivity
bioactive properties
immunosuppressive agents
immunization
Immunosuppressive Agents
Macacine herpesvirus 3
Vaccination
cytokines
vaccination
immune response
Cytokines
antibodies

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus. / Logsdon, Naomi J.; Eberhardt, Meghan K.; Allen, Christopher E.; Barry, Peter A; Walter, Mark R.

In: PLoS One, Vol. 6, No. 11, e28127, 21.11.2011.

Research output: Contribution to journalArticle

Logsdon, Naomi J. ; Eberhardt, Meghan K. ; Allen, Christopher E. ; Barry, Peter A ; Walter, Mark R. / Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus. In: PLoS One. 2011 ; Vol. 6, No. 11.
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