Neutralization of rhesus cytomegalovirus IL-10 reduces horizontal transmission and alters long-term immunity

Jesse D. Deere, W. L. William Chang, Andradi Villalobos, Kimberli A. Schmidt, Ashlesha Deshpande, Luis D. Castillo, Joseph Fike, Mark R. Walter, Peter A Barry, Dennis Hartigan-O'Connor

Research output: Contribution to journalArticle

Abstract

Human cytomegalovirus (HCMV) causes severe disease in infants and immunocompromised people. There is no approved HCMV vaccine, and vaccine development strategies are complicated by evidence of both persistent infection and reinfection of people with prior immunity. The greatest emphasis has been placed on reducing transmission to seronegative pregnant women to prevent vertical transmission and its potentially severe sequelae. Increasing evidence suggests that the earliest host–HCMV interactions establish conditions for viral persistence, including evasion of host immune responses to the virus. Using a nonhuman primate model of HCMV infection, we show that rhesus macaques immunized against viral interleukin-10 (IL-10) manifest delayed rhesus cytomegalovirus (RhCMV) acquisition and altered immune responses to the infection when it does occur. Among animals with the greatest antiviral IL-10–neutralizing activity, the timing of RhCMV seroconversion was delayed by an average of 12 weeks. After acquisition, such animals displayed an antibody response to the new infection, which peaked as expected after 2 weeks but then declined rapidly. In contrast, surprisingly, vaccination with glycoprotein B (gB) protein had no discernible impact on these outcomes. Our results demonstrate that viral IL-10 is a key regulator of successful host immune responses to RhCMV. Viral IL-10 is, therefore, an important target for vaccine strategies against cytomegalovirus (CMV). Furthermore, given the immunoregulatory function of viral IL-10, targeting this protein may prove synergistic with other vaccine therapies and targets. Our study also provides additional evidence that the earliest host–CMV interactions can have a significant impact on the nature of persistent infection.

Original languageEnglish (US)
Pages (from-to)13036-13041
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number26
DOIs
StatePublished - Jan 1 2019

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Cytomegalovirus
Interleukin-10
Immunity
Infection
Cytomegalovirus Vaccines
Vaccines
Immune Evasion
Active Immunotherapy
Cytomegalovirus Infections
Protein Transport
Macaca mulatta
Primates
Antibody Formation
Antiviral Agents
Pregnant Women
Glycoproteins
Vaccination
Viruses

Keywords

  • Cytomegalovirus
  • IL-10
  • Rhesus cytomegalovirus
  • Vaccine
  • Viral IL-10

ASJC Scopus subject areas

  • General

Cite this

Neutralization of rhesus cytomegalovirus IL-10 reduces horizontal transmission and alters long-term immunity. / Deere, Jesse D.; William Chang, W. L.; Villalobos, Andradi; Schmidt, Kimberli A.; Deshpande, Ashlesha; Castillo, Luis D.; Fike, Joseph; Walter, Mark R.; Barry, Peter A; Hartigan-O'Connor, Dennis.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 26, 01.01.2019, p. 13036-13041.

Research output: Contribution to journalArticle

Deere, Jesse D. ; William Chang, W. L. ; Villalobos, Andradi ; Schmidt, Kimberli A. ; Deshpande, Ashlesha ; Castillo, Luis D. ; Fike, Joseph ; Walter, Mark R. ; Barry, Peter A ; Hartigan-O'Connor, Dennis. / Neutralization of rhesus cytomegalovirus IL-10 reduces horizontal transmission and alters long-term immunity. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 26. pp. 13036-13041.
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AU - Schmidt, Kimberli A.

AU - Deshpande, Ashlesha

AU - Castillo, Luis D.

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AU - Barry, Peter A

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AB - Human cytomegalovirus (HCMV) causes severe disease in infants and immunocompromised people. There is no approved HCMV vaccine, and vaccine development strategies are complicated by evidence of both persistent infection and reinfection of people with prior immunity. The greatest emphasis has been placed on reducing transmission to seronegative pregnant women to prevent vertical transmission and its potentially severe sequelae. Increasing evidence suggests that the earliest host–HCMV interactions establish conditions for viral persistence, including evasion of host immune responses to the virus. Using a nonhuman primate model of HCMV infection, we show that rhesus macaques immunized against viral interleukin-10 (IL-10) manifest delayed rhesus cytomegalovirus (RhCMV) acquisition and altered immune responses to the infection when it does occur. Among animals with the greatest antiviral IL-10–neutralizing activity, the timing of RhCMV seroconversion was delayed by an average of 12 weeks. After acquisition, such animals displayed an antibody response to the new infection, which peaked as expected after 2 weeks but then declined rapidly. In contrast, surprisingly, vaccination with glycoprotein B (gB) protein had no discernible impact on these outcomes. Our results demonstrate that viral IL-10 is a key regulator of successful host immune responses to RhCMV. Viral IL-10 is, therefore, an important target for vaccine strategies against cytomegalovirus (CMV). Furthermore, given the immunoregulatory function of viral IL-10, targeting this protein may prove synergistic with other vaccine therapies and targets. Our study also provides additional evidence that the earliest host–CMV interactions can have a significant impact on the nature of persistent infection.

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