Cytomegalovirus (CMV) and all members of Herpesvirales derived from a progenitor herpesvirus (HV) ~200M years ago. As obligate intracellular pathogens, the fact that HV's remain extant to infect their hosts suggests sophisticated viral mechanisms to counter host immune responses. The sophistication of viral immunomodulation is emphasized by the ability of HV's to maintain a lifelong persistence within immune competent hosts. Emerging evidence indicates that a common mechanistic link by which different CMV members attenuate the functionality of host immunity is by targeting the cellular interleukin-10 (cIL-10) signaling pathway. Only primate CMV's (HCMV and RhCMV) encode a viral version of cIL-10 (cmvIL-10 and rhcmvIL-10) that, despite extreme genetic drift from the originally transduced cIL-10 gene, has the identical immunosuppressive properties of cIL10. In parallel approaches conducted in rhesus macaques (RM), we have shown that rhcmvIL-10 is essential for (i) acute and long-term modulation of host immune responses and (ii) enabling long-term shedding of virus in bodily fluids following parenteral RhCMV challenge. Our results indicate that rhcmvIL-10 is a critical viral determinant that skews virus-host interactions towards those that favor the establishment of a persistence in an immune competent host. We hypothesize that immunization of na?ve monkeys against rhcmvIL-10 will significantly increase resistance to mucosally transmitted RhCMV challenge. Our study will demonstrate that vaccine-mediated neutralization of rhcmvIL- 10 can protect against repeated mucosal exposure to RhCMV through the following Aims. (1) Immunization of naive RM with non-functional forms of rhcmvIL-10, RhCMV gB, and rhcmvIL-10 + gB.;(2) Mucosal challenge of immunized RM by introducing them into a cohort of RhCMV- excreting RM under housing conditions that enable horizontal transmission of RhCMV;(3) Development and in vitro characterization of non-functional forms of HCMV cmvIL-10;(4) Vaccination of RM with non-functional HCMV cmvIL-10 and in vitro demonstration of (i) broadly cross-reactive neutralizing antibodies (N-Ab) against HCMV cmvIL-10 sequence variants, and (ii) an absence of antibodies that are cross-reactive with human cIL-10.
Our data in the rhesus model supports the concept that, in the absence of rhcmvIL-10, de novo host immune responses to other viral antigens after RhCMV challenge confer greater protection. Our approach expands historical HCMV vaccine strategies, which have focused on viral proteins encoding neutralizing and cellular epitopes, by targeting cmvIL-10 to neutralize its immunosuppressive properties on host immune responses.
|Deere, Jesse D; Barry, Peter A (2014) Using the nonhuman primate model of HCMV to guide vaccine development. Viruses 6:1483-501|
|Eberhardt, Meghan K; Barry, Peter A (2014) Pathogen manipulation of cIL-10 signaling pathways: opportunities for vaccine development? Curr Top Microbiol Immunol 380:93-128|
|Assaf, Basel T; Mansfield, Keith G; Strelow, Lisa et al. (2014) Limited dissemination and shedding of the UL128 complex-intact, UL/b'-defective rhesus cytomegalovirus strain 180.92. J Virol 88:9310-20|
|Eberhardt, Meghan K; Deshpande, Ashlesha; Chang, W L William et al. (2013) Vaccination against a virus-encoded cytokine significantly restricts viral challenge. J Virol 87:11323-31|
|Logsdon, Naomi J; Eberhardt, Meghan K; Allen, Christopher E et al. (2011) Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus. PLoS One 6:e28127|
|Oxford, Kristie L; Strelow, Lisa; Yue, Yujuan et al. (2011) Open reading frames carried on UL/b' are implicated in shedding and horizontal transmission of rhesus cytomegalovirus in rhesus monkeys. J Virol 85:5105-14|
|Chang, W L William; Barry, Peter A; Szubin, Richard et al. (2009) Human cytomegalovirus suppresses type I interferon secretion by plasmacytoid dendritic cells through its interleukin 10 homolog. Virology 390:330-7|
|Barry, Peter A; Strelow, Lisa (2008) Development of breeding populations of rhesus macaques (Macaca mulatta) that are specific pathogen-free for rhesus cytomegalovirus. Comp Med 58:43-6|
|Oxford, Kristie L; Eberhardt, Meghan K; Yang, Kai-Wen et al. (2008) Protein coding content of the UL)b'region of wild-type rhesus cytomegalovirus. Virology 373:181-8|
|Abel, Kristina; Strelow, Lisa; Yue, Yujuan et al. (2008) A heterologous DNA prime/protein boost immunization strategy for rhesus cytomegalovirus. Vaccine 26:6013-25|
Showing the most recent 10 out of 18 publications