Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques

Benjamin Burwitz, Daniel Malouli, Benjamin N. Bimber, Jason S. Reed, Abigail B. Ventura, Meaghan Hancock, Luke S. Uebelhoer, Amruta Bhusari, Katherine B. Hammond, Renee G. Espinosa Trethewy, Alex Klug, Alfred W. Legasse, Michael Axthelm, Jay Nelson, Byung Park, Daniel Streblow, Scott Hansen, Louis Picker, Klaus Frueh, Jonah Sacha

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Cytomegaloviruses (CMV) are highly species-specific due to millennia of co-evolution and adaptation to their host, with no successful experimental cross-species infection in primates reported to date. Accordingly, full genome phylogenetic analysis of multiple new CMV field isolates derived from two closely related nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM), revealed distinct and tight lineage clustering according to the species of origin, with MCM CMV isolates mirroring the limited genetic diversity of their primate host that underwent a population bottleneck 400 years ago. Despite the ability of Rhesus CMV (RhCMV) laboratory strain 68–1 to replicate efficiently in MCM fibroblasts and potently inhibit antigen presentation to MCM T cells in vitro, RhCMV 68–1 failed to productively infect MCM in vivo, even in the absence of host CD8+ T and NK cells. In contrast, RhCMV clone 68–1.2, genetically repaired to express the homologues of the HCMV anti-apoptosis gene UL36 and epithelial cell tropism genes UL128 and UL130 absent in 68–1, efficiently infected MCM as evidenced by the induction of transgene-specific T cells and virus shedding. Recombinant variants of RhCMV 68–1 and 68–1.2 revealed that expression of either UL36 or UL128 together with UL130 enabled productive MCM infection, indicating that multiple layers of cross-species restriction operate even between closely related hosts. Cumulatively, these results implicate cell tropism and evasion of apoptosis as critical determinants of CMV transmission across primate species barriers, and extend the macaque model of human CMV infection and immunology to MCM, a nonhuman primate species with uniquely simplified host immunogenetics.

Original languageEnglish (US)
Article numbere1006014
JournalPLoS Pathogens
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

Cytomegalovirus Infections
Macaca
Cytomegalovirus
Primates
Tropism
T-Lymphocytes
Reticuloendotheliosis virus
Apoptosis
Virus Shedding
Immunogenetics
Antigen Presentation
Cross Infection
Allergy and Immunology
Macaca mulatta
Transgenes
Natural Killer Cells
Genes
Cluster Analysis
Clone Cells
Fibroblasts

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques. / Burwitz, Benjamin; Malouli, Daniel; Bimber, Benjamin N.; Reed, Jason S.; Ventura, Abigail B.; Hancock, Meaghan; Uebelhoer, Luke S.; Bhusari, Amruta; Hammond, Katherine B.; Espinosa Trethewy, Renee G.; Klug, Alex; Legasse, Alfred W.; Axthelm, Michael; Nelson, Jay; Park, Byung; Streblow, Daniel; Hansen, Scott; Picker, Louis; Frueh, Klaus; Sacha, Jonah.

In: PLoS Pathogens, Vol. 12, No. 11, e1006014, 01.11.2016.

Research output: Contribution to journalArticle

Burwitz, B, Malouli, D, Bimber, BN, Reed, JS, Ventura, AB, Hancock, M, Uebelhoer, LS, Bhusari, A, Hammond, KB, Espinosa Trethewy, RG, Klug, A, Legasse, AW, Axthelm, M, Nelson, J, Park, B, Streblow, D, Hansen, S, Picker, L, Frueh, K & Sacha, J 2016, 'Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques', PLoS Pathogens, vol. 12, no. 11, e1006014. https://doi.org/10.1371/journal.ppat.1006014
Burwitz, Benjamin ; Malouli, Daniel ; Bimber, Benjamin N. ; Reed, Jason S. ; Ventura, Abigail B. ; Hancock, Meaghan ; Uebelhoer, Luke S. ; Bhusari, Amruta ; Hammond, Katherine B. ; Espinosa Trethewy, Renee G. ; Klug, Alex ; Legasse, Alfred W. ; Axthelm, Michael ; Nelson, Jay ; Park, Byung ; Streblow, Daniel ; Hansen, Scott ; Picker, Louis ; Frueh, Klaus ; Sacha, Jonah. / Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques. In: PLoS Pathogens. 2016 ; Vol. 12, No. 11.
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abstract = "Cytomegaloviruses (CMV) are highly species-specific due to millennia of co-evolution and adaptation to their host, with no successful experimental cross-species infection in primates reported to date. Accordingly, full genome phylogenetic analysis of multiple new CMV field isolates derived from two closely related nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM), revealed distinct and tight lineage clustering according to the species of origin, with MCM CMV isolates mirroring the limited genetic diversity of their primate host that underwent a population bottleneck 400 years ago. Despite the ability of Rhesus CMV (RhCMV) laboratory strain 68–1 to replicate efficiently in MCM fibroblasts and potently inhibit antigen presentation to MCM T cells in vitro, RhCMV 68–1 failed to productively infect MCM in vivo, even in the absence of host CD8+ T and NK cells. In contrast, RhCMV clone 68–1.2, genetically repaired to express the homologues of the HCMV anti-apoptosis gene UL36 and epithelial cell tropism genes UL128 and UL130 absent in 68–1, efficiently infected MCM as evidenced by the induction of transgene-specific T cells and virus shedding. Recombinant variants of RhCMV 68–1 and 68–1.2 revealed that expression of either UL36 or UL128 together with UL130 enabled productive MCM infection, indicating that multiple layers of cross-species restriction operate even between closely related hosts. Cumulatively, these results implicate cell tropism and evasion of apoptosis as critical determinants of CMV transmission across primate species barriers, and extend the macaque model of human CMV infection and immunology to MCM, a nonhuman primate species with uniquely simplified host immunogenetics.",
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AU - Hancock, Meaghan

AU - Uebelhoer, Luke S.

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AU - Hammond, Katherine B.

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