Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques.
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.
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Benjamin J
http://orcid.org/0000-0001-7767-022X
BJ
Burwitz
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Daniel
http://orcid.org/0000-0003-1287-7283
D
Malouli
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Benjamin N
BN
Bimber
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Jason S
JS
Reed
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Abigail B
http://orcid.org/0000-0002-8893-4769
AB
Ventura
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Meaghan H
http://orcid.org/0000-0003-2945-0147
MH
Hancock
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Luke S
LS
Uebelhoer
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Amruta
A
Bhusari
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Katherine B
KB
Hammond
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Renee G
http://orcid.org/0000-0002-9262-4587
RG
Espinosa Trethewy
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Alex
A
Klug
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Alfred W
AW
Legasse
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Michael K
MK
Axthelm
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Jay A
JA
Nelson
Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Byung S
http://orcid.org/0000-0003-3516-7516
BS
Park
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Daniel N
DN
Streblow
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Scott G
http://orcid.org/0000-0002-9845-6481
SG
Hansen
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Louis J
LJ
Picker
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Klaus
K
Früh
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Jonah B
JB
Sacha
D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000635:transmission*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D059014:High-Throughput Nucleotide Sequencing; D008252:Macaca fascicularis / Q000821:virology*; D008253:Macaca mulatta / Q000821:virology*; D010802:Phylogeny; D013045:Species Specificity
D004279:DNA, Viral