title: Reconstitution of Human Cytomegalovirus-Specific CD4+ T Cells is Critical for Control of Virus Reactivation in Hematopoietic Stem Cell Transplant Recipients but Does Not Prevent Organ Infection.
abstract: The relative contribution of human cytomegalovirus (HMCV)-specific CD4(+) and CD8(+) T cells to the control of HCMV infection in hematopoietic stem cell transplant (HSCT) recipients is still controversial. HCMV reactivation and HCMV-specific CD4(+) and CD8(+) T cell reconstitution were monitored for 1 year in 63 HCMV-seropositive patients receiving HSCT. HCMV reactivation was detected in all but 2 patients. In 20 of 63 (31.7%) patients (group 1) HCMV infection resolved spontaneously, whereas 32 of 63 (50.8%) patients (group 2) controlled the infection after a single short-course of pre-emptive therapy and the remaining 9 (14.3%) patients (group 3) suffered from relapsing episodes of HCMV infection, requiring multiple courses of antiviral therapy. The kinetics and magnitude of HCMV-specific CD8(+) T cell reconstitution were comparable among the 3 groups, but HCMV-specific CD4(+) T cells were lower in number in patients requiring antiviral treatment. HCMV-seronegative donors, as well as unrelated donors (receiving antithymocyte globulin) and acute graft-versus-host disease (GVHD) were associated with both delayed HCMV-specific CD4(+) T cell reconstitution and severity of infection. Conversely, these risk factors had no impact on HCMV-specific CD8(+) T cells. Eight patients with previous GVHD suffered from HCMV gastrointestinal disease, although in the presence of HCMV-specific CD4(+) and CD8(+) systemic immunity and undetectable HCMV DNA in blood. Reconstitution of systemic HCMV-specific CD4(+) T cell immunity is required for control of HCMV reactivation in adult HSCT recipients, but it may not be sufficient to prevent late-onset organ localization in patients with GVHD. HCMV-specific CD8(+) T cells contribute to control of HCMV infection, but only after HCMV-specific CD4(+) T cell reconstitution.
authors.affiliation: Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gabanti
authors.affiliation: Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lilleri
authors.affiliation: Divisione di Ematologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ripamonti
authors.affiliation: Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bruno
authors.affiliation: Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zelini
authors.affiliation: SS Virologia Molecolare, SC Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Furione
authors.affiliation: Divisione di Ematologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Colombo
authors.affiliation: Divisione di Ematologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Alessandrino
authors.affiliation: Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: g.gerna@smatteo.pv.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gerna
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D002908:Chronic Disease; D003587:Cytomegalovirus / Q000276:immunology / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014775:Virus Activation
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents
keywords: CD4(+) T cells; CD8(+) T cells; Gastrointestinal disease; Hematopoietic stem cell transplantation; Human cytomegalovirus; Specific T cell immunity