title: Prevention strategies differentially modulate the impact of cytomegalovirus replication on CD8(+) T-cell differentiation in high-risk solid organ transplant patients.
abstract: The present study aimed to determine whether antiviral prevention strategies against cytomegalovirus (CMV) infection used in high-risk D+R- solid organ transplanted patients can modulate the impact of CMV replication on CD8(+) T-cell differentiation. The different CD8(+) T-cell subpopulations were measured at a single point when at least one year had elapsed since transplantation. A total of 68 D+R- patients were included, of which 33 underwent pre-emptive therapy and 35 received prophylaxis. Multivariate analysis showed that CMV replication was associated with the expansion of CD28־ EMRA CD8(+) T cells in patients managed pre-emptively but not in patients under prophylaxis (21.4% vs. 3.6%). This finding is likely related to the higher frequency of CMV recurrence observed in patients under pre-emptive therapy compared to those under prophylaxis (75% vs. 14.3%; p < 0.001). In fact, multivariate analysis showed that having more than one replication episode was associated with a 17.2% increase (p = 0.001) in the percentage of CD28־ EMRA CD8(+) T cells compared to "no episode" and with a 10.9% increase with respect to "single episodes" (p = 0.025). Additionally, patients with IFNγ response to CMV (QuantiFERON-CMV Reactive) had a higher percentage of late-differentiated CD8(+) T cells than patients lacking this response. In summary, recurrent CMV replication in D+R- patients under pre-emptive therapy was associated with the expansion of CD28־ EMRA CD8(+) T cells, which might have a short-term beneficial effect related to the high functionality of this T-cell subpopulation. Nevertheless, we cannot rule out that this accumulation might have a long-term detrimental effect related to immunosenescence and inflammation.
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Cantisán
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Páez-Vega
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital/ CSIC/University of Sevilla, Unit of Infectious Diseases, Microbiology and Preventive Medicine, Sevilla, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Pérez-Romero
authors.affiliation: Infectious Diseases Unit, Cruces University Hospital, Bilbao, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Montejo
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital/ CSIC/University of Sevilla, Unit of Infectious Diseases, Microbiology and Preventive Medicine, Sevilla, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cordero
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain; Department of Microbiology, Reina Sofia University Hospital, Cordoba, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gracia-Ahufinger
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital/ CSIC/University of Sevilla, Unit of Infectious Diseases, Microbiology and Preventive Medicine, Sevilla, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martín-Gandul
authors.affiliation: Department of Nephrology, Cruces University Hospital, Bilbao, Spain.
authors.forename: Naroa
authors.initials: N
authors.lastname: Maruri
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Aguado
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain; Department of Immunology, Reina Sofia University Hospital, Cordoba, Spain. Electronic address: rsolana@uco.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Solana
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain; Infectious Diseases Unit, Reina Sofia University Hospital, Cordoba, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Torre-Cisneros
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000821:virology*; D002454:Cell Differentiation; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000453:epidemiology / Q000209:etiology* / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation / Q000009:adverse effects*; D063868:Patient Outcome Assessment; D065129:Pre-Exposure Prophylaxis; D019562:Viral Load; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D015415:Biomarkers; D007074:Immunoglobulin G
keywords: Antiviral prevention strategies; CMV replication; D+R- patients; Interferon-gamma; Late-differentiated CD8(+) T cells; Solid organ transplantation