Postnatal acquisition of primary rhesus cytomegalovirus infection is associated with prolonged virus shedding and impaired CD4+ T lymphocyte function.
BACKGROUND
Although virus-specific CD4(+) T lymphocytes emerge rapidly during primary cytomegalovirus (CMV) infection in humans, they exhibit a state of prolonged functional exhaustion of unknown etiology. To investigate the suitability of rhesus macaques as a model of primary human CMV infection, we examined the virologic and immunologic features of naturally acquired primary CMV infection in rhesus macaques.


METHODS
CMV-specific CD4(+) T lymphocytes and CMV load in blood, saliva, and urine were evaluated in a cohort of simian immunodeficiency virus (SIV)-negative rhesus macaques stratified by age into infant, juvenile, and adult groups.


RESULTS
CMV infection was detected in juvenile and adult monkeys but not in infant monkeys. CMV loads and shedding frequency in urine and saliva were significantly higher in the 2-3-year old juvenile monkeys, compared with the adult monkeys. The increased CMV load in juvenile monkeys was associated with lower polyfunctionality, impaired proliferation, and increased expression of the inhibitory receptor PD-1 in CMV-specific CD4(+) T lymphocytes. The proliferative defect was partially reversible by exogenous PD-1 blockade or addition of interleukin 2.


CONCLUSIONS
Postnatal acquisition of primary CMV infection in rhesus macaques results in prolonged virus excretion and impaired CMV-specific CD4(+) T-lymphocyte function, findings that recapitulate key features of primary CMV infection in humans.
Institute for Medical Immunology, Université Libre de Bruxelles, Belgium.
Pierre
P
Antoine
Division of Immunology.
Valerie
V
Varner
Primate Medicine, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts.
Angela
A
Carville
Division of Immunology.
Michelle
M
Connole
Institute for Medical Immunology, Université Libre de Bruxelles, Belgium.
Arnaud
A
Marchant
Division of Immunology.
Amitinder
A
Kaur
D000818:Animals; D001769:Blood / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003430:Cross-Sectional Studies; D003587:Cytomegalovirus / Q000302:isolation & purification*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D008253:Macaca mulatta; D018419:Primate Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology; D012463:Saliva / Q000821:virology; D014556:Urine / Q000821:virology; D019562:Viral Load; D017201:Virus Shedding
CD4+ T lymphocyte; IFN-γ; IL-2; PD-1; TNF-α; cytomegalovirus; functional exhaustion; primary cytomegalovirus infection; rhesus macaque; viral excretion