title: Primary response against cytomegalovirus during antiviral prophylaxis with valganciclovir, in solid organ transplant recipients.
abstract: Antiviral prophylaxis has proved successful for prevention of cytomegalovirus (CMV) disease in solid organ transplant (SOT) patients; though emerging data suggest that antiviral agents interfere with immunity, and may inhibit immune priming. In this context, we investigated levels and phenotype of primary CMV-specific immune responses that developed during antiviral prophylaxis in a cohort of CMV seronegative recipients (R(-) ) of a SOT from a seropositive donor (D(+) ). We longitudinally monitored CMV viral load, antibodies and levels of the negative immuno-modulator IL-10. PBMC were stimulated with CMV-specific peptide libraries to measure CD137 activation marker on CMV-specific T-cells and levels of PD-1 receptor, which is over expressed on exhausted T-cells. Unexpectedly, the majority (13/18) of D(+) R(-) patients who developed a primary CMV response showed early post-transplant CMV-specific responses, though levels of PD-1 on CMV-specific T-cells remained elevated throughout prophylaxis. A strong inverse association was found between levels of plasma IL-10 and CMV-specific cellular immune responses. Our study suggests that during prophylaxis, subclinical CMV infection might have occurred in the D(+) R(-) patients, and primary CMV-specific responses were detected early post-transplant when levels of plasma IL-10 were low. Extended prophylaxis or antiviral treatment did not appear to suppress CMV-specific antibodies or T-cells, which, however, showed exhaustion phenotypes.
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA 91010, USA. clarosa@coh.org
authors.forename: Corinna
authors.initials: C
authors.lastname: La Rosa
authors.forename: Ajit P
authors.initials: AP
authors.lastname: Limaye
authors.forename: Aparna
authors.initials: A
authors.lastname: Krishnan
authors.forename: Gideon
authors.initials: G
authors.lastname: Blumstein
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000328:Adult; D000368:Aged; D000956:Antigens, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D016030:Kidney Transplantation / Q000379:methods*; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D000077562:Valganciclovir; D019562:Viral Load; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D000998:Antiviral Agents; D017874:Immediate-Early Proteins; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; C044582:immediate-early proteins, cytomegalovirus; D016753:Interleukin-10; D000077562:Valganciclovir; D015774:Ganciclovir