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    PD-1 expression and IL-2 loss of cytomegalovirus- specific T cells correlates with viremia and reversible functional anergy. Sester U,Presser D,Dirks J,Gärtner B C,Köhler H,Sester M American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Cytomegalovirus (CMV) represents a major cause of infectious complications after transplantation. Recently, chronic infections with lymphocyte choriomeningitis virus (LCMV), HIV or HCV were shown to be associated with functionally exhausted T cells characterized by high expression of the programmed death (PD)-1 molecule and altered cytokine expression patterns. We therefore hypothesized that functional exhaustion of CMV-specific CD4 T cells may determine impaired CMV control in patients after renal transplantation. In viremic transplant recipients, a significantly higher proportion of CMV-specific CD4 T cells was PD-1 positive (median 40.9%, 17.0-88.7%) as compared to nonviremic transplant patients (8.8%, 0.8-80.5%), dialysis patients (8.8%, 0-36.7%) or controls (3.2%, 0.3-15.4%, p < 0.0001). In line with functional impairment, PD-1-positive T cells produced significantly less IFNgamma as compared to PD-1-negative T cells (p < 0.0001). Moreover, unlike controls or nonviremic patients, CMV-specific T cells from viremic patients showed a significant loss of IL-2 production (p < 0.0001). Interestingly, functional anergy of CMV-specific CD4 T cells was reversible in that antibody-mediated blockade of PD-1 signaling with its ligands PD-L1/-L2 led to an up to 10-fold increase in CMV-specific proliferation. In conclusion, expression of PD-1 defines a reversible defect of CMV-specific CD4 T cells that is associated with viremia, and blocking PD-1 signaling may provide a potential target for enhancing the function of exhausted T cells in chronic CMV infection. 10.1111/j.1600-6143.2008.02279.x
    B and T lymphocyte attenuator is highly expressed on CMV-specific T cells during infection and regulates their function. Serriari Nacer-Eddine,Gondois-Rey Françoise,Guillaume Yves,Remmerswaal Ester B M,Pastor Sonia,Messal Nassima,Truneh Alemseged,Hirsch Ivan,van Lier René A W,Olive Daniel Journal of immunology (Baltimore, Md. : 1950) B and T lymphocyte attenuator (BTLA), like its relative programmed cell death-1 (PD-1), is a receptor that negatively regulates murine T cell activation. However, its expression and function on human T cells is currently unknown. We report in this study on the expression of BTLA in human T cell subsets as well as its regulation on virus-specific T cells during primary human CMV infection. BTLA is expressed on human CD4(+) T cells during different stages of differentiation, whereas on CD8(+) T cells, it is found on naive T cells and is progressively downregulated in memory and differentiated effector-type cells. During primary CMV infection, BTLA was highly induced on CMV-specific CD8(+) T cells immediately following their differentiation from naive cells. After control of CMV infection, BTLA expression went down on memory CD8(+) cells. Engagement of BTLA by mAbs blocked CD3/CD28-mediated T cell proliferation and Th1 and Th2 cytokine secretion. Finally, in vitro blockade of the BTLA pathway augmented, as efficient as anti-PD-1 mAbs, allogeneic as well as CMV-specific CD8(+) T cell proliferation. Thus, our results suggest that, like PD-1, BTLA provides a potential target for enhancing the functional capacity of CTLs in viral infections. 10.4049/jimmunol.0902487
    Overview: cytomegalovirus and the herpesviruses in transplantation. Fishman J A American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Herpesviruses infect most animal species. Infections due to the eight human herpesviruses (HHV) are exacerbated by immunosuppression in organ transplantation. The special features of the herpesvirus life cycle include the ability to establish latent, nonproductive infection and the life-long capacity for reactivation to productive, lytic infection. Interactions between latent virus and the immune system determine the frequency and severity of symptomatic infections. The immunologic and cellular effects of herpesvirus infections contribute to risk for opportunistic infections and graft rejection. Among the most important advances in transplantation are laboratory assays for the diagnosis and monitoring of herpesvirus infections and antiviral agents with improved efficacy in prophylaxis and therapy. For herpes simplex virus, varicella zoster virus and cytomegalovirus, these advances have significantly reduced the morbidity of infection. The syndromes of EBV-associated posttransplant lymphoproliferative disorders (PTLD) and Kaposi's sarcoma remain important complications of immunosuppression. The epidemiology and essential biology of human herpesvirus is reviewed. 10.1111/ajt.12002
    Cytomegalovirus infection in transplant recipients. Azevedo Luiz Sergio,Pierrotti Lígia Camera,Abdala Edson,Costa Silvia Figueiredo,Strabelli Tânia Mara Varejão,Campos Silvia Vidal,Ramos Jéssica Fernandes,Latif Acram Zahredine Abdul,Litvinov Nadia,Maluf Natalya Zaidan,Caiaffa Filho Helio Hehl,Pannuti Claudio Sergio,Lopes Marta Heloisa,Santos Vera Aparecida dos,Linardi Camila da Cruz Gouveia,Yasuda Maria Aparecida Shikanai,Marques Heloisa Helena de Sousa Clinics (Sao Paulo, Brazil) Cytomegalovirus infection is a frequent complication after transplantation. This infection occurs due to transmission from the transplanted organ, due to reactivation of latent infection, or after a primary infection in seronegative patients and can be defined as follows: latent infection, active infection, viral syndrome or invasive disease. This condition occurs mainly between 30 and 90 days after transplantation. In hematopoietic stem cell transplantation in particular, infection usually occurs within the first 30 days after transplantation and in the presence of graft-versus-host disease. The major risk factors are when the recipient is cytomegalovirus seronegative and the donor is seropositive as well as when lymphocyte-depleting antibodies are used. There are two methods for the diagnosis of cytomegalovirus infection: the pp65 antigenemia assay and polymerase chain reaction. Serology has no value for the diagnosis of active disease, whereas histology of the affected tissue and bronchoalveolar lavage analysis are useful in the diagnosis of invasive disease. Cytomegalovirus disease can be prevented by prophylaxis (the administration of antiviral drugs to all or to a subgroup of patients who are at higher risk of viral replication) or by preemptive therapy (the early diagnosis of viral replication before development of the disease and prescription of antiviral treatment to prevent the appearance of clinical disease). The drug used is intravenous or oral ganciclovir; oral valganciclovir; or, less frequently, valacyclovir. Prophylaxis should continue for 90 to 180 days. Treatment is always indicated in cytomegalovirus disease, and the gold-standard drug is intravenous ganciclovir. Treatment should be given for 2 to 3 weeks and should be continued for an additional 7 days after the first negative result for viremia. 10.6061/clinics/2015(07)09
    The "ABC" of Virus-Specific T Cell Immunity in Solid Organ Transplantation. Sester M,Leboeuf C,Schmidt T,Hirsch H H American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Transplant patients are at increased risk of viral complications due to impaired control of viral replication, resulting from HLA mismatching between graft and host and the immunosuppression needed to avert alloimmune reactions. In the past decade, quantitative viral load measurements have become widely available to identify patients at risk and to inform treatment decisions with respect to immunosuppressive drugs and antiviral therapies. Because viral loads are viewed as the result of viral replication and virus-specific immune control, virus-specific T cell monitoring has been explored to optimize management of adenovirus, BK polyomavirus and cytomegalovirus ("ABC") in transplant patients. Although most studies are descriptive using different technologies, the overall results show that the quantity and quality of virus-specific T cells inversely correlate with viral replication, whereby strong cellular immune responses are associated with containment of viral replication. The key obstacles to the introduction of assays for virus-specific T cells into clinical practice is the definition of reliable cutoffs for clinical decision making, the poor negative predictive value of some assays, and the absence of interventional trials justifying changes of antiviral treatment or immunosuppression. More clinical research is needed using optimized assays and targets before standardization and commutability can be envisaged as achieved for viral load testing. 10.1111/ajt.13684
    The Immunology of Posttransplant CMV Infection: Potential Effect of CMV Immunoglobulins on Distinct Components of the Immune Response to CMV. Carbone Javier Transplantation The immune response to cytomegalovirus (CMV) infection is highly complex, including humoral, cellular, innate, and adaptive immune responses. Detection of CMV by the innate immune system triggers production of type I IFNs and inflammatory cytokines which initiate cellular and humoral responses that are critical during the early viremic phase of CMV infection. Sustained control of CMV infection is largely accounted for by cellular immunity, involving various T-cell and B-cell subsets. In solid organ transplant patients, global suppression of innate and adaptive immunities by immunosuppressive agents limits immunological defense, including inhibition of natural killer cell activity with ongoing lowering of Ig levels and CMV-specific antibody titers. This is coupled with a short-term suppression of CMV-specific T cells, the extent and duration of which can predict risk of progression to CMV viremia. CMV immunoglobulin (CMVIG) preparations have the potential to exert immunomodulatory effects as well as providing passive immunization. Specific CMVIG antibodies and virus neutralization might be enhanced by modulation of dendritic cell activity and by a decrease in T-cell activation, effects which are of importance during the initial phase of infection. In summary, the role of CMVIG in reconstituting specific anti-CMV antibodies may be enhanced by some degree of modulation of the innate and adaptive immune responses, which could help to control some of the direct and indirect effects of CMV infection. 10.1097/TP.0000000000001095
    Herpesviridae. Definition, provisional nomenclature, and taxonomy. The Herpesvirus Study Group, the International Committee on Taxonomy of Viruses. Roizman B,Carmichael L E,Deinhardt F,de-The G,Nahmias A J,Plowright W,Rapp F,Sheldrick P,Takahashi M,Wolf K Intervirology 10.1159/000149269
    Partial restoration of cytokine profile despite reconstitution of cytomegalovirus-specific cell-mediated immunity in human immunodeficiency virus-infected patients during highly active antiretroviral treatment. Alfonzo M,Blanc D,Troadec C,Eliaszewicz M,Gónzalez G,Scott-Algara D Scandinavian journal of immunology We reconstituted cytomegalovirus (CMV)-specific T-cell responses in human immunodeficiency virus-1-positive, CMV-positive patients receiving highly active antiretroviral treatment (HAART). We used several combinations of functionality parameters to determine the degree of T-lymphocyte reconstitution obtained during 1 year of treatment. Untreated patients displayed CMV-specific cytotoxic T-lymphocyte (CTL) activity despite the absence of CMV-specific lymphoproliferative responses (LPRs) and despite the fact that interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) were not secreted. The absence of LPRs, IFN-gamma and IL-2 before antiretroviral treatment suggests that CMV-specific immunity was deregulated despite the high CD4+ T-cell counts presented by our cohort, which are critical to the reactivation of CMV disease. After 6 months of HAART, CTL activity had increased compared with the baseline, as had the levels of secreted IFN-gamma and LPR. However, the levels of specific IL-2 produced did not change during therapy, and no specific IL-2 was detected during the follow-up period. Taken together, our findings suggest that 1 year of HAART led to the recovery of some, but not all, CMV-specific responses in our cohort of patients.
    Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. Bunde Torsten,Kirchner Alexander,Hoffmeister Bodo,Habedank Dirk,Hetzer Roland,Cherepnev Georgy,Proesch Susanna,Reinke Petra,Volk Hans-Dieter,Lehmkuhl Hans,Kern Florian The Journal of experimental medicine T cells are crucial for the control of cytomegalovirus (CMV) in infected individuals. Although CMV-specific T cells can be quantified by various methods, clear correlates of protection from CMV disease have not been defined. However, responses to the pp65 protein are believed to play an important role. Here, the proportions of interferon gamma-producing T cells following ex vivo activation with pools of overlapping peptides representing the pp65 and immediate early (IE)-1 proteins were determined at multiple time points and related to the development of CMV disease in 27 heart and lung transplant recipients. Frequencies of IE-1-specific CD8 T cells above 0.2 and 0.4% at day 0 and 2 wk, respectively, or 0.4% at any time during the first months discriminated patients who did not develop CMV disease from patients at risk, 50-60% of whom developed CMV disease. No similar distinction between risk groups was possible based on pp65-specific CD8 or CD4 T cell responses. Remarkably, CMV disease developed exclusively in patients with a dominant pp65-specific CD8 T cell response. In conclusion, high frequencies of IE-1 but not pp65-specific CD8 T cells correlate with protection from CMV disease. These results have important implications for monitoring T cell responses, adoptive cell therapy, and vaccine design. 10.1084/jem.20042384
    The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen. Suwelack Barbara,Malyar Viola,Koch Martina,Sester Martina,Sommerer Claudia Transplantation reviews (Orlando, Fla.) The increasing incidence of BK-associated nephropathy following kidney transplantation has prompted an examination of strategies for risk reduction and management through immunosuppression manipulation. Evidence from retrospective and prospective studies suggests that BK viruria and viremia, and the need for BK virus treatment, are higher with tacrolimus than cyclosporine. Combined therapy with tacrolimus and mycophenolic acid may be associated with a particularly higher risk of BK infection, but data are conflicting as to whether mycophenolic acid per se is an independent risk factor. The incidence of BK-related events may be reduced in patients receiving mTOR inhibitors (everolimus or sirolimus) with cyclosporine vs a calcineurin inhibitor with mycophenolic acid. De novo immunosuppression regimens that avoid rabbit antithymocyte globulin and tacrolimus, particularly tacrolimus with mycophenolic acid, may be advantageous, whereas low-exposure cyclosporine with an mTOR inhibitor appears a favorable option. Routine screening for BK infection during the first 2 years posttransplant is recommended to allow preemptive modification of the immunosuppressive regimen. In patients at high risk of BK virus infection, appropriate de novo immunosuppression or very early conversion to an mTOR inhibitor to facilitate reduction or discontinuation of calcineurin inhibitors or antimetabolites should be considered. Extensive further research into optimal avoidance, screening, and treatment strategies is required. 10.1016/j.trre.2011.05.002
    Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells. Dirks J,Egli A,Sester U,Sester M,Hirsch H H Transplant infectious disease : an official journal of the Transplantation Society BACKGROUND:Programmed death receptor-1 (PD-1) compromises cytomegalovirus (CMV)-specific T-cell responses and has been linked to CMV viremia after transplantation. An impaired functional and proliferative capacity of PD-1-positive CMV-specific T cells may be reversed by the antibody-mediated blockade of PD-1 signaling. However, knowledge is limited on changes in "cytokinome" expression profiles associated with reversal of functional exhaustion. METHODS:The "cytokinome" was analyzed by 27-plex Luminex technology comparing renal transplant recipients with low (n = 5) and high (n = 5) PD-1 expression on CMV-specific T cells. The effect of blocking PD-1 by PD-ligand (PD-L) antibodies on restoration of cytokine expression was examined. RESULTS:CMV-specific cytokine release and proliferation was lower in patients with high PD-1 expression on CMV-specific T cells. Antibody-mediated blockade of PD-L in CMV-stimulated samples restored expression levels of interleukin (IL)-1β, IL-2, IL-6, IL-9, IL-10, granulocyte colony-stimulating factor, interferon-γ, macrophage inflammatory protein-1α, and tumor necrosis factor-α. By contrast, no profound effect was observed for controls or patients with low PD-1 expression, or in staphylococcal enterotoxin B-stimulated cells. CONCLUSION:Taken together, this pilot study provides evidence that a high PD-1 expression on CMV-specific T cells actively impairs proliferation and "cytokinome" responses in an antigen-specific manner. Importantly, blockade of PD-L restores CMV-specific T-cell proliferation and expression of a panel of different proinflammatory and/or type 1 cytokines, suggesting a common but as yet unknown regulatory principle. We conclude that PD-1 exhaustion is reversible and potentially amenable to therapeutic ex vivo and possibly in vivo manipulation. However, detailed knowledge of the differential effects on the "cytokinome" will be necessary to increase the safety and the efficacy of such manipulations. 10.1111/tid.12025
    Cytomegalovirus in solid organ transplantation. Razonable R R,Humar A, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 10.1111/ajt.12103
    Restoration of CMV-specific-CD4 T cells with ART occurs early and is greater in those with more advanced immunodeficiency. Hsu Denise C,Kerr Stephen J,Iampornsin Thatri,Pett Sarah L,Avihingsanon Anchalee,Thongpaeng Parawee,Zaunders John J,Ubolyam Sasiwimol,Ananworanich Jintanat,Kelleher Anthony D,Cooper David A PloS one OBJECTIVES:Restoration of Cytomegalovirus-specific-CD4 T cell (CMV-Sp-CD4) responses partly accounts for the reduction of CMV-disease with antiretroviral-therapy (ART), but CMV-Sp-CD4 may also drive immune activation and immunosenescence. This study characterized the dynamics of CMV-Sp-CD4 after ART initiation and explored associations with CD4 T cell recovery as well as frequency of naïve CD4 T cells at week 96. METHODS:Fifty HIV-infected, ART-naïve Thai adults with CD4 T cell count ≤ 350 cells/µL and starting ART were evaluated over 96 weeks (ClinicalTrials.gov identifier NCT01296373). CMV-Sp-CD4 was detected by co-expression of CD25/CD134 by flow cytometry after CMV-antigen stimulation. RESULTS:All subjects were CMV sero-positive, 4 had quantifiable CMV-DNA (range 2.3-3.9 log10 copies/mL) at baseline but none had clinically apparent CMV-disease. Baseline CMV-Sp-CD4 response was positive in 40 subjects. Those with CD4 T cell count < 100 cells/µL were less likely to have positive baseline CMV-Sp-CD4 response (P=0.003). Positive baseline CMV-Sp-CD4 response was associated with reduced odds of quantifiable CMV-DNA (P=0.022). Mean CD4 T cell increase at week 96 was 213 cells/µL. This was associated positively with baseline HIV-VL (P=0.001) and negatively with age (P=0.003). The frequency of CMV-Sp-CD4 increased at week 4 (P=0.008), then declined. Those with lower baseline CMV-Sp-CD4 (P=0.009) or CDC category C (P<0.001) had greater increases in CMV-Sp-CD4 at week 4. At week 96, CD4 T cell count was positively (P<0.001) and the frequency of CMV-Sp-CD4 was negatively (P=0.001) associated with the percentage of naïve CD4 T cells. CONCLUSIONS:Increases in CMV-Sp-CD4 with ART occurred early and were greater in those with more advanced immunodeficiency. The frequency of CMV-Sp-CD4 was associated with reduced naïve CD4 T cells, a marker associated with immunosenescence. 10.1371/journal.pone.0077479
    The impact of viral load and time to onset of cytomegalovirus replication on long-term graft survival after kidney transplantation. Reischig Tomas,Kacer Martin,Hruba Petra,Jindra Pavel,Hes Ondrej,Lysak Daniel,Bouda Mirko,Viklicky Ondrej Antiviral therapy BACKGROUND:Asymptomatic cytomegalovirus (CMV) infection is associated with graft dysfunction and failure. However, no study assessed CMV viral load in terms of the risk for graft failure. METHODS:In a prospective cohort of kidney transplant recipients, we assessed the impact of CMV DNAemia on the overall graft survival and the incidence of moderate-to-severe interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsy at 36 months. CMV DNAemia was stratified by viral load in whole blood. RESULTS:A total of 180 patients transplanted from October 2003 through January 2011 were included and followed for 4 years; 87 (48%) patients received 3-month prophylaxis with valacyclovir and 45 (25%) with valganciclovir; 48 (27%) were managed by pre-emptive therapy. Within 12 months of transplantation, CMV DNAemia developed in 102 (57%) patients with 36 (20%) having a viral load of ≥2,000 copies/ml. Multivariate Cox analysis identified CMV DNAemia as an independent risk factor for graft loss (hazard ratio 3.42; P=0.020); however, after stratification by viral load, only CMV DNAemia ≥2,000 copies/ml (hazard ratio 7.62; P<0.001) remained significant. Both early-onset (<3 months; P=0.048) and late-onset (>3 months; P<0.001) CMV DNAemia ≥2,000 copies/ml were risk factors for graft loss. The incidence of moderate-to-severe IF/TA was not significantly influenced by CMV DNAemia. CONCLUSIONS:Kidney transplant recipients having CMV DNAemia with a higher viral load irrespective of the time to onset are at increased risk for graft loss. 10.3851/IMP3129
    Primary Cytomegalovirus Infection in Seronegative Kidney Transplant Patients Is Associated with Protracted Cold Ischemic Time of Seropositive Donor Organs. Schlott Fabian,Steubl Dominik,Hoffmann Dieter,Matevossian Edouard,Lutz Jens,Heemann Uwe,Hösel Volker,Busch Dirk H,Renders Lutz,Neuenhahn Michael PloS one Human Cytomegalovirus (CMV) can lead to primary infection or reactivation in CMV-seronegative or -seropositive kidney transplant recipients, respectively. Complications comprise severe end-organ diseases and acute or chronic transplant rejection. Risk for CMV manifestation is stratified according to the CMV-IgG-serostatus, with donor+/recipient- (D+/R-) patients carrying the highest risk for CMV-replication. However, risk factors predisposing for primary infection in CMV-seronegative recipients are still not fully elucidated. Therefore, we monitored D+/R- high-risk patients undergoing kidney transplantation in combination with antiviral prophylaxis for the incidence of CMV-viremia for a median follow-up time of 784 days (156-1155 days). In this period, we analyzed the functional CMV-specific T cell response by intracellular cytokine staining and CMV-serology by ELISA. Only four of eight D+/R- patients developed clinically relevant CMV-viremia followed by seroconversion. Viremia triggered expansion of functional CMV-specific T cells correlating with protection against secondary CMV-reactivations. In contrast, all other patients remained permanently aviremic and showed no immunological correlate of infection after discontinuation of antiviral prophylaxis for up to three years. Comparing cold ischemic times (CIT) of viremic (median = 1020 min; 720-1080 min) and aviremic patients (median = 335 min; 120-660 min) revealed significantly (p = 0.0286) protracted CIT in patients with primary CMV-infection. Taken together, primary CMV-infection affects only a subgroup of D+/R- patients correlating with length of CIT. Therefore, patients with extended CIT should be thoroughly monitored for CMV-replication well beyond discontinuation of antiviral prophylaxis. In contrast, patients with short CIT remained permanently uninfected and might benefit from shorter prophylactic treatment. 10.1371/journal.pone.0171035
    CMV-specific T-cell immunity in solid organ transplant recipients at low risk of CMV infection. Chronology and applicability in preemptive therapy. Mena-Romo Juan Damián,Pérez Romero Pilar,Martín-Gandul Cecilia,Gentil Miguel Ángel,Suárez-Artacho Gonzalo,Lage Ernesto,Sánchez Magdalena,Cordero Elisa The Journal of infection OBJECTIVES:To characterize whether the CMV-specific cellular immune response can be used as a predictor of the control of CMV infection and disease and determine thresholds in solid organ transplant (SOT) recipients seropositive for CMV (R+). METHODS:The CMV-specific T-cell response was characterized using intracellular cytokine staining and the evolution of clinical and virological parameters were recorded during the first year after transplantation. RESULTS:Besides having positive CMV serology, only 28.4% patients had positive immunity (CD8CD69IFN-γ ≥0.25%) at 2 weeks after transplantation. These patients had less indication of preemptive treatment (p = 0.025) and developed less high grade (≥2000 IU/ml) CMV replication episodes (p = 0.006) than patients with no immunity. Of the 49 patients with a pretransplant sample, only 22.4% had positive immunity, and had a detectable immune response early after transplantation (median of 3.7 weeks). However, only 50% of patients with negative pretransplant immunity acquired a positive immune response and it was significantly later, at a median of 11 weeks (p < 0.001). Patients that developed CMV disease had no CMV-specific immunity. CONCLUSIONS:Having CMV-specific CD8IFN-γ cells ≥0.25% before transplant; 0.15% at two weeks or 0.25% at four weeks after transplantation, identifies patients that may spontaneously control CMV infection and may require less monitoring. 10.1016/j.jinf.2017.05.020
    Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management. Devakumar Delan,Bamford Alasdair,Ferreira Marcelo U,Broad Jonathan,Rosch Richard E,Groce Nora,Breuer Judith,Cardoso Marly A,Copp Andrew J,Alexandre Paula,Rodrigues Laura C,Abubakar Ibrahim The Lancet. Infectious diseases Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities. 10.1016/S1473-3099(17)30398-5
    Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies. Litjens Nicolle H R,Huang Ling,Dedeoglu Burç,Meijers Ruud W J,Kwekkeboom Jaap,Betjes Michiel G H Frontiers in immunology The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMV patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMV patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137IFNγCD4 and CD137IFNγCD8 memory T cells were present in 46 and 39% of CMV patients ( = 28) although at much lower frequencies compared to CMV patients (median 0.01 versus 0.58% for CD4 and 0.05 versus 0.64% for CD8 T cells) with a less differentiated CD28-expressing phenotype. In line with these data, CMV-specific proliferative CD4 and CD8 T cells were observed in CMV patients, which significantly correlated with the frequency of CMV-specific T cells. CMV-specific IgG antibody-secreting cells (ASC) could be detected at low frequency in 36% of CMV patients (1 versus 45 ASC/10 cells in CMV patients). CMV patients with pretransplant CMV-specific CD137IFNγCD4 T cells had a lower risk to develop CMV viremia after transplantation with a CMV donor kidney (relative risk: 0.43,  = 0.03). In conclusion, a solitary CMV-specific T-cell response without detectable anti-CMV antibodies is frequent and clinically relevant as it is associated with protection to CMV infection following transplantation with a kidney from a CMV donor. 10.3389/fimmu.2017.01137
    An Early Immediate Early Protein IE-1-Specific T-Cell Polyfunctionality Is Associated With a Better Control of Cytomegalovirus Reactivation in Kidney Transplantation. Dekeyser Manon,Ladrière Marc,Audonnet Sandra,Frimat Luc,De Carvalho Bittencourt Marcelo Kidney international reports 10.1016/j.ekir.2017.02.016
    Lack of evidence of association between IFNG and IL28B polymorphisms and QuantiFERON-CMV test results in seropositive transplant patients. Aguado Rocío,Páez-Vega Aurora,Agüera María L,Montejo Miguel,Guirado Lluis,Fortún Jesús,Suárez-Benjumea Alejandro,Len Oscar,Fariñas María C,de Gracia Carmen,Hernández Domingo,Cobos-Ceballos María J,Torre-Cisneros Julián,Cantisán Sara, , Human immunology The aim of this study was to analyze the relationship between the IFNG +874 T/A and IL28B (rs12979860) C/T polymorphisms and the secretion of IFNG by CD8+ T cells after stimulation with cytomegalovirus (CMV) peptides, measured using QuantiFERON-CMV (QF-CMV) assay. A total of 184 CMV-seropositive solid organ transplant patients (108 kidney, 68 liver and 8 lung) were recruited. Of them, 151 patients were QF-CMV Reactive (IFNG ≥ 0.2 UI/mL) and 33 were Non-reactive. Genotype frequencies in the study population were TT (26.6%), AT (50.0%) and AA (23.4%) for IFNG +874 and CC (52.7%), CT (39.1%) and TT (8.2%) for IL28B (rs12979860). These frequencies did not significantly differ between QF-CMV Reactive and Non-reactive patients. Nor were any significant differences observed in the quantitative IFNG level among the genotypes in either the IFNG or the IL28 genes. When we analyzed whether these polymorphisms had any impact on the risk of CMV replication after transplantation, the adjusted analysis showed no association. In summary, our results showed that IFNG +874 T/A and IL28B (rs12979860) C/T polymorphisms are not associated with the IFNG response to CMV measured by the QuantiFERON-CMV assay, although these results should be confirmed with a higher number of patients. 10.1016/j.humimm.2018.03.009
    Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives. Hodowanec Aimee C,Pikis Andreas,Komatsu Takashi E,Sampson Mario R,Younis Islam R,O'Rear Julian J,Singer Mary E Journal of clinical pharmacology This review summarizes the significant impact of cytomegalovirus (CMV) infection on solid organ and hematopoietic stem cell transplant recipients. A discussion of the various CMV prevention and treatment strategies is provided, including a detailed description of each of the available CMV antiviral drugs. 10.1002/jcph.1363
    Prenatal Cytomegalovirus Infection: Timing Is Everything. Pass Robert F Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 10.1093/cid/ciy1129
    Differential Pathogen-Specific Immune Reconstitution in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Children. Muenchhoff Maximilian,Adland Emily,Roider Julia,Kløverpris Henrik,Leslie Alasdair,Boehm Stephan,Keppler Oliver T,Ndung'u Thumbi,Goulder Philip J R The Journal of infectious diseases BACKGROUND:Susceptibility to coinfections in human immunodeficiency virus (HIV)-infected patients remains increased despite antiretroviral therapy (ART). To elucidate mechanisms involved in immune reconstitution, we studied immune activation, immune exhaustion, and HIV- and copathogen-specific T-cell responses in children before and after ART. METHODS:We prospectively enrolled 25 HIV-infected children to study HIV-, cytomegalovirus (CMV)-, and tuberculosis (TB)-specific T-cell responses before and 1 year after initiation of ART using intracellular cytokine (interleukin-2, interferon-γ, tumor necrosis factor-α) staining assays after in vitro stimulation. We further measured expression of activation, immune exhaustion, and memory phenotype markers and studied proliferative responses after antigen stimulation. RESULTS:We observed differential, pathogen-specific changes after 1 year of ART in cytokine profiles of CD4 T-cell responses that were associated with shifts in memory phenotype and decreased programmed cell death 1 (PD-1) expression. The proliferative capacity of HIV- and PPD-specific responses increased after 1 year of ART. Of note, the recovery of CMV- and TB-specific responses was correlated with a decrease in PD-1 expression (r = 0.83, P = .008 and r = 0.81, P = .0007, respectively). CONCLUSIONS:Reconstitution of immune responses on ART is associated with alterations in T-cell phenotype, function, and PD-1 expression that are distinct for HIV, TB, and CMV. The PD-1 pathway represents a potential target for immunotherapy in HIV-infected patients on ART with insufficient immune reconstitution. 10.1093/infdis/jiy668
    Cellular immune responses to cytomegalovirus in renal transplant recipients. Radha Raju,Jordan Stanley,Puliyanda Dechu,Bunnapradist Suphamai,Petrosyan Anna,Amet Nurmamet,Toyoda Mieko American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Control of CMV replication depends primarily on anti-CMV T lymphocyte activity. However, the functional T-cell responses to CMV in immunosuppressed solid organ transplant recipients are not well understood. In this study we employed cytokine flowcytometry (CFC) using pooled CMV peptides and viral lysates to detect CMV-specific T-cell responses in 17 healthy controls, 33 stable renal transplant recipients (Tx recipients) and 6 transplant recipients with active CMV infection (CMV(+)). We found that pooled peptides and lysates provide optimal detection of IFN gamma production in anti-CMV CD8(+) and CD4(+) T cells, respectively. In both healthy controls and Tx recipients, CMV-specific T-cell levels strongly correlated with serostatus. Seropositive Tx recipients have significantly higher levels of CMV-specific CD8(+) T-cell responses compared to healthy controls, which may signify an effort to control enhanced viral replication in immunosuppressed Tx recipients. In some individuals, absence of anti-CMV T-cell response may correlate with lack of viral clearance by ganciclovir therapy, even when CMV isolates are not ganciclovir resistant. Thus, monitoring cellular immunity with CFC along with viral load by PCR merits further exploration for identification of patients at the risk of developing CMV disease, tailoring prophylactic and therapeutic decisions and preventing complications. 10.1111/j.1600-6143.2003.00647.x
    CMV-Specific T Cell Monitoring Offers Superior Risk Stratification of CMV-Seronegative Kidney Transplant Recipients of a CMV-Seropositive Donor. Schachtner Thomas,Stein Maik,Reinke Petra Transplantation BACKGROUND:Detectable cytomegalovirus (CMV)-specific T cells in CMV-seronegative kidney transplant recipients (KTRs) have been attributed to an absence of circulating antibodies despite CMV sensitization. The diagnostic value of CMV-specific T cells, however, needs to be implemented in risk stratification for CMV replication. METHODS:Three hundred twenty-six KTRs were studied and classified with respect to CMV serostatus and presence of CMV-specific T cells. Samples were collected pretransplantation, at +1, +2, and +3 months posttransplantation. CMV-specific T cells directed to CMV-IE1 and CMV-pp65 were measured by interferon-γ Elispot assay. RESULTS:Nineteen (28%) of 67 D+R- KTRs showed pretransplant CMV-specific T cells. Although no differences were observed for CMV replication, KTRs with CMV-specific T cells presented with lower initial and peak CMV loads (P < 0.05). KTRs with decreasing/undetectable CMV-IE1-specific T cells pretransplantation and posttransplantation were at greatest risk of CMV replication. KTRs with stable/increasing CMV-IE1-specific T cells from pretransplantation to posttransplantation, however, showed low risk of CMV replication (P < 0.001). One hundred sixty-two (80%) of 203 R+ KTRs showed pretransplant CMV-specific T cells. Decreasing/undetectable CMV-IE1-specific T cells from pretransplantation and posttransplantation identified those R+ KTRs at increased risk of CMV replication (65/80 KTRs; 81%; P < 0.001). CONCLUSIONS:Despite CMV prophylaxis, D+R- KTRs are at greatest risk of CMV disease. Our data suggest that monitoring CMV-specific T cell kinetics from pretransplantation to posttransplantation, particularly directed to CMV-IE1, offers superior risk stratification compared with CMV serostatus alone. 10.1097/TP.0000000000001825
    A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients. Kumar Deepali,Chin-Hong Peter,Kayler Liise,Wojciechowski David,Limaye Ajit P,Osama Gaber A,Ball Simon,Mehta Aneesh K,Cooper Matthew,Blanchard Ted,MacDougall James,Kotton Camille N American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons T cell immunity is essential for the control of cytomegalovirus (CMV) infection after transplantation. We evaluated a CMV-specific peptide-based enzyme-linked immunosorbent spot (ELISPOT) assay to determine whether assay results could predict subsequent CMV events. Adult kidney transplant recipients at 43 centers underwent ELISPOT testing to enumerate interferon gamma (IFN-γ) binding spot-forming units (sfu) after stimulation of cells with an overlapping peptide pool of CMV phosphoprotein 65 (pp65) and immediate early-1 (IE-1) protein at the end of antiviral prophylaxis (EOP) and various time points thereafter. The primary outcome was a CMV event in the first posttransplant year. In 583 kidney transplant recipients (260 seropositive donor [D+]/seronegative recipient [R-] and 277 R+), CMV events occurred in 44 of 368 eligible patients (11.8%) at a median of 227 days (range 92-360) posttransplant. A cutoff value of >40 sfu/2.5 × 10  cells for either IE-1 or pp65 was derived as a threshold for positivity, with a negative predictive value of >97% for CMV events. CMV events were significantly lower in assay positive vs assay negative patients (3.0% vs 19.5%, P < .0001 for pp65). Time to CMV event post-EOP was significantly greater in those with sfu >40 at EOP (P < .0001). In this large, multicenter trial of kidney transplant recipients, we show that an assessment of CMV-specific immunity using a novel ELISPOT assay is able to predict protection from CMV infection. 10.1111/ajt.15315
    Improving our mechanistic understanding of the indirect effects of CMV infection in transplant recipients. L'Huillier Arnaud G,Ferreira Victor H,Ku Terrance,Bahinskaya Ilona,Kumar Deepali,Humar Atul American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Cytomegalovirus (CMV) is an immunomodulatory virus that indirectly increases the risk for bacterial, fungal, and viral infections. However, the pathogenesis of this phenomenon is poorly understood. We determined whether inflammatory responses to different Toll-like receptor (TLR) ligands are blunted during CMV infection in solid-organ transplant (SOT) patients. Peripheral blood mononuclear cells from 38 SOT patients with and without CMV were incubated in the presence of various viral, fungal, and bacterial TLR ligands. Cytokines were measured in the supernatant by multiplex enzyme-linked immunosorbent assay. Patients had blunted cytokine responses to bacterial, fungal, and viral ligands during CMV infection when compared to the absence of CMV infection. This was independent of viral load, clinical presentation of CMV infection or immunosuppression, supporting the clinical observation in SOT recipients that CMV infection increases susceptibility to bacterial, fungal, and other viral infections. Moreover, in the absence of CMV infection, patients with subsequent CMV infection had lower cytokines in response to TLR ligands compared to those without subsequent CMV infection, suggesting that inherent differences in patients not directly related to CMV also contribute to this increased susceptibility. In summary, these data provide novel ex vivo evidence to support indirect effects of CMV. 10.1111/ajt.15371
    Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients. Egli Adrian,Binet Isabelle,Binggeli Simone,Jäger Clemens,Dumoulin Alexis,Schaub Stefan,Steiger Juerg,Sester Urban,Sester Martina,Hirsch Hans H Journal of translational medicine BACKGROUND:Cytomegalovirus (CMV) seronegative recipients (R-) of kidney transplants (KT) from seropositive donors (D+) are at higher risk for CMV replication and ganciclovir(GCV)-resistance than CMV R(+). We hypothesized that low CMV-specific T-cell responses are associated with increased risk of CMV replication in R(+)-patients with D(+) or D(-) donors. METHODS:We prospectively evaluated 73 consecutive KT-patients [48 R(+), 25 D(+)R(-)] undergoing routine testing for CMV replication as part of a preemptive strategy. We compared CMV-specific interferon-gamma (IFN-gamma) responses of CD4+CD3+ lymphocytes in peripheral blood mononuclear cells (PBMC) using three different antigen preparation (CMV-lysate, pp72- and pp65-overlapping peptide pools) using intracellular cytokine staining and flow cytometry. RESULTS:Median CD4+ and CD8+T-cell responses to CMV-lysate, pp72- and pp65-overlapping peptide pools were lower in D(+)R(-) than in R(+)patients or in non-immunosuppressed donors. Comparing subpopulations we found that CMV-lysate favored CD4+- over CD8+-responses, whereas the reverse was observed for pp72, while pp65-CD4+- and -CD8+-responses were similar. Concurrent CMV replication in R(+)-patients was associated with significantly lower T-cell responses (pp65 median CD4+ 0.00% vs. 0.03%, p = 0.001; CD8+ 0.01% vs. 0.03%; p = 0.033). Receiver operated curve analysis associated CMV-pp65 CD4+ responses of > 0.03% in R(+)-patients with absence of concurrent (p = 0.003) and future CMV replication in the following 8 weeks (p = 0.036). GCV-resistant CMV replication occurred in 3 R(+)-patients (6.3%) with pp65- CD4+ frequencies < 0.03% (p = 0.041). CONCLUSION:The data suggest that pp65-specific CD4+ T-cells might be useful to identify R(+)-patients at increased risk of CMV replication. Provided further corroborating evidence, CMV-pp65 CD4+ responses above 0.03% in PBMCs of KT patients under stable immunosuppression are associated with lower risk of concurrent and future CMV replication during the following 8 weeks. 10.1186/1479-5876-6-29
    Cytomegalovirus and human immunosenescence. Pawelec Graham,Derhovanessian Evelyna,Larbi Anis,Strindhall Jan,Wikby Anders Reviews in medical virology 'Immunosenescence' is an imprecise term used to describe deleterious age-associated changes to immune parameters observed in all mammals studied so far. Primarily anecdotal evidence implies that failing immunity is responsible for the increased incidence and severity of infectious disease in old people. However, there is a serious dearth of accurate hard data concerning the actual cause of death in the elderly and the contribution thereto of the multitude of age-associated alterations measured in the immune system. Cross-sectional studies comparing those currently young with those currently old reveal a large number of differences in the distribution of immune cell types in the blood, and to some extent the functional integrity of those cells. Many of these parameters differ markedly between individuals infected with CMV and uninfected people, regardless of infection with other persistent herpesviruses. The adaptive arm of immunity appears to be more seriously affected than the innate arm, particularly the T lymphocytes. However, cross-sectional studies suffer the disadvantage that like is not being compared with like, because the conditions applied during the entire life course of the currently elderly were different from those applied now to the young. These differences in environment, nutrition, pathology and possibly genetics, rather than merely age, may be expected to influence the parameters studied. Moreover, pathogen exposure of the currently elderly was also different from contemporary exposure, probably including CMV. Some of the problems associated with cross-sectional studies can be overcome by performing longitudinal studies, as pointed out in an earlier analysis of the Baltimore Longitudinal Ageing study looking at lymphocyte numbers. However, longitudinal studies are challenging in humans. Nonetheless, the pioneering Swedish OCTO/NONA studies of the very elderly which for the first time included a range of immune parameters, have identified a set of immune parameters predicting mortality at 2, 4 and 6 year follow-up; CMV infection makes a material contribution to this so-called 'immune risk profile (IRP)'. Whether the IRP is informative in younger individuals and the mechanism of the CMV effect is discussed in this review. 10.1002/rmv.598
    Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Sester Urban,Gärtner Barbara C,Wilkens Heinrike,Schwaab Bernhard,Wössner Rolf,Kindermann Ingrid,Girndt Matthias,Meyerhans Andreas,Mueller-Lantzsch Nikolaus,Schäfers Hans-Joachim,Sybrecht Gerhard W,Köhler Hans,Sester Martina American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r =-0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation. 10.1111/j.1600-6143.2005.00871.x
    Dysregulated cytokine responses during cytomegalovirus infection in renal transplant recipients. Sadeghi Mahmoud,Daniel Volker,Naujokat Cord,Schnitzler Paul,Schmidt Jan,Mehrabi Arianeb,Zeier Martin,Opelz Gerhard Transplantation OBJECTIVE:Pre- and posttransplant predisposing factors for cytomegalovirus (CMV) activation and disease are not well defined. The aim of this study was to examine whether there are differences in plasma cytokine levels pretransplant, before and during CMV replication in renal transplant recipients. MATERIAL AND METHODS:We studied 76 renal transplant recipients in whom CMV-DNA was studied at regular intervals posttransplant. Thirty-eight patients developed CMV viremia posttransplant (CMV-DNA-positive). Thirty-eight patients had no detectable CMV-DNA posttransplant (CMV-DNA-negative). Cytokine and cytokine receptors/antagonists plasma levels were measured pretransplant, and pre-, during, and after CMV-viremia in CMV-DNA-positive patients and at similar time points in CMV-DNA-negative transplant recipients. RESULTS:Compared with pretransplant, after transplantation soluble (s) plasma interleukin (IL)-2 receptor (R), IL-6, and interferon-gamma (IFN-gamma) decreased in both groups (CMV-DNA-positive: P=0.002; P=0.028; P=0.032; CMV-DNA-negative: P=0.001; P=0.040; P=0.030) whereas IL-10 remained constant in both groups (P=n.s.). During CMV viremia, sIL-2R (P=0.015) and IL-6 (P=0.006) increased compared with previremia but remained constant in CMV-DNA-negative patients matched for the day of investigation (P=n.s.). Simultaneously, IFN-gamma increased in CMV-DNA-negative patients (P=0.008) and remained constant in CMV-DNA-positive patients (P=n.s.). During CMV viremia, IL-10 (P=0.002) and sIL-2R (P=0.007) were significantly higher in CMV-DNA-positive than CMV-DNA-negative patients investigated at similar time points. CONCLUSION:Our results indicate that CMV replication in renal transplant recipients is associated with increased sIL-2R, IL-6, and IL-10 and decreased IFN-gamma plasma levels, pointing to a monocyte/Th2 activation and a Th1 blockade. The high IL-10 might decrease the IFN-gamma plasma levels in CMV-DNA-positive patients. Th1 deficiency in CMV-DNA-positive patients might promote development of CMV disease. 10.1097/TP.0b013e31817b063d
    A prospective longitudinal analysis of cytomegalovirus (CMV)-specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection. Eid Albert J,Brown Robert A,Arthurs Supha K,Lahr Brian D,Eckel-Passow Jeanette E,Larson Timothy S,Razonable Raymund R Transplant international : official journal of the European Society for Organ Transplantation Cytomegalovirus (CMV)-specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV-specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine-flow cytometry, we enumerated interferon-gamma producing CMV-specific CD4+ and CD8+ T cells at serial time points among CMV-mismatched (D+/R-) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (+ or - SD) time of 151 (+ or - 33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue-invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R-) status (HR: 13, 95% CI: 1.6-106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1-27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change-over-time in CMV-specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE-1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV-specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV-specific T cell assays will need to be assessed in a larger cohort of CMV D+/R- kidney recipients who remain at high-risk of delayed-onset CMV disease. 10.1111/j.1432-2277.2009.01017.x
    Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Manuel Oriol,Husain Shahid,Kumar Deepali,Zayas Carlos,Mawhorter Steve,Levi Marilyn E,Kalpoe Jayant,Lisboa Luiz,Ely Leticia,Kaul Daniel R,Schwartz Brian S,Morris Michele I,Ison Michael G,Yen-Lieberman Belinda,Sebastian Anthony,Assi Maha,Humar Atul Clinical infectious diseases : an official publication of the Infectious Diseases Society of America BACKGROUND:Cytomegalovirus (CMV) disease remains an important problem in solid-organ transplant recipients, with the greatest risk among donor CMV-seropositive, recipient-seronegative (D(+)/R(-)) patients. CMV-specific cell-mediated immunity may be able to predict which patients will develop CMV disease. METHODS:We prospectively included D(+)/R(-) patients who received antiviral prophylaxis. We used the Quantiferon-CMV assay to measure interferon-γ levels following in vitro stimulation with CMV antigens. The test was performed at the end of prophylaxis and 1 and 2 months later. The primary outcome was the incidence of CMV disease at 12 months after transplant. We calculated positive and negative predictive values of the assay for protection from CMV disease. RESULTS:Overall, 28 of 127 (22%) patients developed CMV disease. Of 124 evaluable patients, 31 (25%) had a positive result, 81 (65.3%) had a negative result, and 12 (9.7%) had an indeterminate result (negative mitogen and CMV antigen) with the Quantiferon-CMV assay. At 12 months, patients with a positive result had a subsequent lower incidence of CMV disease than patients with a negative and an indeterminate result (6.4% vs 22.2% vs 58.3%, respectively; P < .001). Positive and negative predictive values of the assay for protection from CMV disease were 0.90 (95% confidence interval [CI], .74-.98) and 0.27 (95% CI, .18-.37), respectively. CONCLUSIONS:This assay may be useful to predict if patients are at low, intermediate, or high risk for the development of subsequent CMV disease after prophylaxis. CLINICAL TRIALS REGISTRATION:NCT00817908. 10.1093/cid/cis993
    Comparison of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV quantiferon gamma interferon-releasing assays in assessing risk of CMV infection in kidney transplant recipients. Abate Davide,Saldan Alda,Mengoli Carlo,Fiscon Marta,Silvestre Cristina,Fallico Loredana,Peracchi Marta,Furian Lucrezia,Cusinato Riccardo,Bonfante Luciana,Rossi Barbara,Marchini Francesco,Sgarabotto Dino,Rigotti Paolo,Palù Giorgio Journal of clinical microbiology Assessing cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) represents an appealing strategy for identifying transplant recipients at risk of infection. In this study, we compared two gamma interferon-releasing assays (IGRAs), Quantiferon-CMV and CMV enzyme-linked immunosorbent spot (ELISPOT), to determine the ability of each test to predict protective CMV-specific T-cell responses. Two hundred twenty-one Quantiferon-CMV and ELISPOT tests were conducted on 120 adult kidney transplant recipients (KTRs), including 100 CMV-seropositive transplant recipients (R+) and 20 CMV-seronegative transplant recipients of a CMV-positive donor (D+/R-). As a control cohort, 39 healthy adult subjects (including 33 CMV-seropositive and 6 CMV-seronegative subjects) were enrolled. CMV IgG serology was used as a reference for both tests. In the CMV-seropositive individuals, the ELISPOT and Quantiferon-CMV assays provided 46% concordance with the serology, 12% discordance, 18% disagreement between ELISPOT or Quantiferon-CMV and the serology, and 24% gray areas when one or both tests resulted in weak positives. None of the CMV-seronegative subjects showed detectable responses in the ELISPOT or the Quantiferon-CMV test. In transplant recipients, both the ELISPOT and Quantiferon-CMV assays positively correlated with each other and negatively correlated with CMV DNAemia in a significant way (P<0.05). During the antiviral prophylaxis, all 20 D+/R- KTRs we examined displayed undetectable Quantiferon-CMV and ELISPOT results, and there was no evidence of CMV seroconversion. The receiving operator curve (ROC) statistical analysis revealed similar specificities and sensitivities in predicting detectable viremia (areas under the curve [AUC], 0.66 and 0.62 for Quantiferon-CMV and ELISPOT, respectively). ELISPOT and Quantiferon-CMV values of >150 spots/200,000 peripheral blood mononuclear cells (PBMCs) and >1 to 6 IU gamma interferon (IFN-γ) were associated with protection from CMV infection (odds ratios [OR], 5 and 8.75, respectively). In transplant recipients, the two tests displayed similar abilities for predicting CMV infection. Both the ELISPOT and Quantiferon-CMV assays require several ameliorations to avoid false-negative results. 10.1128/JCM.00563-13
    Cytomegalovirus (CMV)-Specific Perforin and Granzyme B ELISPOT Assays Detect Reactivation of CMV Infection in Inflammatory Bowel Disease. Nowacki Tobias M,Bettenworth Dominik,Ross Matthias,Heidemann Jan,Lehmann Paul V,Lügering Andreas Cells The role of cytomegalovirus (CMV) infection in the pathogenesis and exacerbation of Inflammatory Bowel Disease (IBD) has been unresolved. Typically, the CMV genome remains dormant in infected cells, but a breakdown of immune surveillance can lead to re-activation of viral replication in the gut mucosa, which is not necessarily associated with viremia or changes in antibody titers. We hypothesized that the detection of CMV-specific CD8 effector T cells should permit the distinction between dormant and active CMV infection. As CD8 effector T cells, unlike memory CD8 T cells, have perforin (PFN) and granzyme B (GzB) preformed in their cytoplasmic granules, we employed single cell resolution ELISPOT assays to measure the CMV antigen-triggered release of these molecules by CD8 T cells isolated from subjects with IBD, and age-matched healthy controls. The frequencies of CMV-specific (GzB) and PFN-producing CD8 T cells were increased in IBD patients compared to healthy controls. Furthermore, the increased CMV reactivity was associated with active IBD disease and with longer disease duration. Notably, PCR on serum frequently failed to detect CMV DNA during flares. The data show that during active IBD there is a flare of CD8 T cell activity against CMV in a substantial proportion of IBD patients, suggesting CMV reactivation that serum PCR does not detect. While it remains open whether CMV reactivation is a cause or consequence of IBD, our data suggest that monitoring CMV antigen-specific effector CD8 T cells with GzB and PFN ELISPOT analysis can provide novel insights into the role of CMV infection in IBD. Additionally, our data have implications for the fields of transplantation, HIV, cancer, and autoimmune diseases, in all of which patient care critically depends on sensitive and reliable detection of a reactivation of CMV infection. 10.3390/cells1020035
    Virus-Specific CD8(+) T Cells Cross-Reactive to Donor-Alloantigen Are Transiently Present in the Circulation of Kidney Transplant Recipients Infected With CMV and/or EBV. Heutinck K M,Yong S L,Tonneijck L,van den Heuvel H,van der Weerd N C,van der Pant K A M I,Bemelman F J,Claas F H J,Ten Berge I J M American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons T cells play a dual role in transplantation: They mediate transplant rejection and are crucial for virus control. Memory T cells generated in response to pathogens can cross-react to alloantigen, a phenomenon called heterologous immunity. Virus-specific CD8(+) T cells cross-reacting to donor-alloantigen might affect alloimmune responses and hamper tolerance induction following transplantation. Here, we longitudinally studied these cross-reactive cells in peripheral blood of 25 kidney transplant recipients with a cytomegalovirus and/or Epstein-Barr virus infection. Cross-reactive T cells were identified by flow cytometry as virus-specific T cells that proliferate in response to donor cells in a mixed-lymphocyte reaction. In 13 of 25 patients, we found cross-reactivity to donor cells for at least 1 viral epitope before (n = 7) and/or after transplantation (n = 8). Cross-reactive T cells were transiently present in the circulation, and their precursor frequency did not increase following transplantation or viral infection. Cross-reactive T cells expressed interferon-γ and CD107a in response to both alloantigen and viral peptide and resembled virus-specific T cells in phenotype and function. Their presence was not associated with impaired renal function, proteinuria, or rejection. In conclusion, virus-specific T cells that cross-react to donor-alloantigen are transiently detectable in the circulation of kidney transplant recipients. 10.1111/ajt.13618
    Impact of donor and recipient human cytomegalovirus status on kidney transplantation. Zielinski Maciej,Tarasewicz Agnieszka,Zielinska Hanna,Jankowska Magdalena,Moszkowska Grazyna,Debska-Slizien Alicja,Rutkowski Boleslaw,Trzonkowski Piotr International immunology Human cytomegalovirus (HCMV) is considered to be a major pathogen that affects the outcome of solid organ transplantation (TX). Both recipient and donor may be HCMV positive, therefore HCMV re-infection is possible after TX. However, little is known how cytomegalovirus (CMV) transmitted from an infected donor to an infected recipient modulates the recipient's already suppressed immunity, and what the clinical consequences are. To investigate these issues, 52 kidney recipients were followed up for 2 years after TX. T, B and natural killer (NK) lymphocytes, naive and memory T subsets, CD28 expression, relative telomere length, CMV-specific lymphocytes and serum cytokines were measured several times post-TX. Patients were monitored for signs of CMV viremia and other infections. The most important observation was that CMV-specific lymphocytes expand vastly in HCMV-infected recipients who received kidneys from infected donors, in comparison with uninfected donors. Despite this, a higher rate of HCMV viremia was found. Immune deterioration was confirmed by an increased number of CD28-negative T lymphocytes, inverted CD4/CD8 index and shortened telomeres. This was superior in HCMV-infected recipients transplanted from infected donors, when compared with uninfected. In conclusion, CMV alters the immune system in kidney transplant recipients and promotes immune exhaustion. 10.1093/intimm/dxx062
    Diagnostic utility of monitoring cytomegalovirus-specific immunity by QuantiFERON-cytomegalovirus assay in kidney transplant recipients. Deborska-Materkowska Dominika,Perkowska-Ptasinska Agnieszka,Sadowska Anna,Gozdowska Jolanta,Ciszek Michał,Serwanska-Swietek Marta,Domagala Piotr,Miszewska-Szyszkowska Dorota,Sitarek Elzbieta,Jozwik Agnieszka,Kwiatkowski Artur,Durlik Magdalena BMC infectious diseases BACKGROUND:Despite universal prophylaxis, late cytomegalovirus (CMV) infection occurs in a high proportion of kidney transplant recipients. We evaluated whether a specific viral T-cell response allows for the better identification of recipients who are at high risk of CMV infection after prophylaxis withdrawal. METHODS:We conducted a prospective study in 19 pretransplant anti-CMV seronegative kidney graft recipients R- (18 from seropositive donors [D+] and one from a seronegative donor [D-]) and 67 seropositive recipients R(+) (59 from seropositive donors and eight from seronegative donors) who received antiviral prophylaxis with valganciclovir. The QuantiFERON-CMV (QF-CMV) assay was performed within the first and third months after transplantation. Blood samples were monitored for CMV DNAemia using a commercial quantitative nucleic acid amplification test (QNAT) that was calibrated to the World Health Organization International Standard. RESULTS:Twenty-one of the 86 patients (24%) developed CMV viremia after prophylaxis withdrawal within 12 months posttransplantation. In the CMV R(+) group, the QF-CMV assay yielded reactive results (QF-CMV[+]) in 51 of 67 patients (76%) compared with 7 of 19 patients (37%) in the CMV R(-) group (p = 0.001). In the CMV R(+) group, infection occurred in seven of 16 recipients (44%) who were QF-CMV(-) and eight of 51 recipients (16%) who were QF-CMV(+). In the CMV R(-) group, infection evolved in five of 12 recipients (42%) who were QF-CMV(-) and one of 7 recipients (14%) who were QF-CMV(+). No difference was found in the incidence of CMV infection stratified according to the QF-CMV results with regard to the recipients' pretransplant CMV IgG serology (p = 0.985). Cytomegalovirus infection occurred in 15 of 36 patients (42%) with hypogammaglobulinemia (HGG) 90 days posttransplantation compared with two of 34 patients (6%) without HGG (p = 0.0004). Cytomegalovirus infection occurred in seven of 13 patients (54%) with lymphocytopenia compared with 14 of 70 patients (20%) without lymphocytopenia (p = 0.015). The multivariate analysis revealed that the nonreactive QuantiFERON-CMV assay was an independent risk factor for postprophylaxis CMV infection. CONCLUSIONS:In kidney transplant recipients who received posttransplantation prophylaxis, negative QF-CMV results better defined the risk of CMV infection than initial CMV IgG status after prophylaxis withdrawal. Hypogammaglobulinemia and lymphocytopenia were risk factors for CMV infection. 10.1186/s12879-018-3075-z
    New Developments in the Management of Cytomegalovirus Infection After Transplantation. Meesing Atibordee,Razonable Raymund R Drugs Cytomegalovirus (CMV) continues to be one of the most important pathogens that universally affect solid organ and allogeneic hematopoietic stem cell transplant recipients. Lack of effective CMV-specific immunity is the common factor that predisposes to the risk of CMV reactivation and clinical disease after transplantation. Antiviral drugs are the cornerstone for prevention and treatment of CMV infection and disease. Over the years, the CMV DNA polymerase inhibitor, ganciclovir (and valganciclovir), have served as the backbone for management, while foscarnet and cidofovir are reserved for the management of CMV infection that is refractory or resistant to ganciclovir treatment. In this review, we highlight the role of the newly approved drug, letermovir, a viral terminase inhibitor, for CMV prevention after allogeneic hematopoietic stem cell transplantation. Advances in immunologic monitoring may allow for an individualized approach to management of CMV after transplantation. Specifically, the potential role of CMV-specific T-cell measurements in guiding the need for the treatment of asymptomatic CMV infection and the duration of treatment of CMV disease is discussed. The role of adoptive immunotherapy, using ex vivo-generated CMV-specific T cells, is highlighted. This article provides a review of novel drugs, tests, and strategies in optimizing our current approaches to prevention and treatment of CMV in transplant recipients. 10.1007/s40265-018-0943-1
    Enhancement of Cytomegalovirus-Specific Cytokine Production after Modulation of the Costimulation in Kidney Transplant Patients. Dornieden Theresa,Wilde Benjamin,Korth Johannes,Werner Kai,Horn Peter A,Witzke Oliver,Lindemann Monika Journal of immunology research Kidney transplantation is the therapy of choice for patients with end stage renal disease. Due to immunosuppressive treatment, patients are at risk for opportunistic infections. Cytomegalovirus (CMV) reactivation is highly relevant in kidney transplant recipients because it occurs-depending on the serological constellation of the donor and recipient-in more than half of the patients and influences patient outcome. Patients with CMV reactivation show decreased allograft and overall survival. Previous studies could demonstrate that transplant patients often show weak CMV-specific immunity. Besides immunosuppressive treatment, additional mechanisms may reduce CMV-specific immunocompetence such as enhanced negative costimulation. Hence, the aim of this study was to investigate if the function of CMV-specific cells of kidney transplant recipients could be restored by a modulation of costimulatory molecules. To address this question, lymphocytes of kidney transplant patients were stimulated with CMV-specific antigens and incubated with programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), or B- and T-lymphocyte attenuator (BTLA) antibodies. Afterwards, the IFN-, IL-21, and IL-17A production was measured by the ELISpot assay. It could be shown that a blockade of the ligand PD-L1 resulted in an increased CMV-specific IFN-, IL-21, and IL-17A secretion. The blockade of the receptor PD-1 distinctly enhanced the production of IL-21. BTLA antibodies, however, led only to a marginal increase of CMV-specific IFN- and of IL-21 production. Experiments in healthy controls could confirm the results of the kidney transplant recipients. Furthermore, they could demonstrate that treatment with the immunosuppressive drug tacrolimus resulted in decreased CMV-specific IFN- and of IL-21 production. Thus, our study could show for the first time that the blockade of the PD-L1/PD-1 pathway also modulates CMV-specific Th21 and Th17 cell function in kidney transplant recipients. Further studies are mandatory to clarify the role of Th21 and Th17 cells in CMV control of these patients. 10.1155/2019/3926175
    Revisiting cytomegalovirus serostatus and replication as risk factors for inferior long-term outcomes in the current era of renal transplantation. Bischof Nicole,Wehmeier Caroline,Dickenmann Michael,Hirt-Minkowski Patricia,Amico Patrizia,Steiger Jürg,Naegele Klaudia,Hirsch Hans H,Schaub Stefan Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:Cytomegalovirus (CMV) serostatus and CMV replication are considered as risk factors for inferior graft and patient survival after renal transplantation, but long-term outcome data are limited. The aim of this retrospective single-centre study was to investigate the impact of CMV serostatus and CMV replication/disease on long-term outcomes in a well-defined cohort managed by a standardized CMV prevention/treatment protocol. METHODS:We investigated 599 consecutive kidney transplantations having a CMV prevention protocol consisting of either prophylaxis (D+/R- and R+ with ATG induction) or screening/deferred therapy (R+ without ATG induction). Patients were grouped according to CMV serostatus [high risk (D+/R-): n = 122; intermediate risk (R+): n = 306; low risk (D-/R-): n = 171] and occurrence of CMV replication/disease (no CMV replication: n = 419; asymptomatic CMV replication: n = 110; CMV syndrome: n = 39; tissue-invasive CMV disease: n = 31). The median follow-up time was 6.5 years. RESULTS:Graft and patient survival were not different among the three CMV serostatus groups as well as the four CMV replication/disease groups (P ≥ 0.44). Eighty-seven patients died, 17 due to infections (21%), but none was attributable to CMV. The overall hospitalization incidence for CMV-related infection was 3% (17/599 patients). The incidence of clinical and (sub)clinical rejection was similar among the groups (P ≥ 0.17). In a multivariate Cox proportional hazard model, neither CMV serostatus, nor CMV replication, nor CMV disease were independent predictors for patient death or graft failure, respectively. CONCLUSIONS:This retrospective single-centre study suggests that the negative impact of CMV infection on long-term patient and allograft survival as well as on allograft rejection can be largely eliminated with current diagnostic/therapeutic management. 10.1093/ndt/gfz268
    Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial. Jarque Marta,Crespo Elena,Melilli Edoardo,Gutiérrez Alex,Moreso Francesc,Guirado Lluís,Revuelta Ignacio,Montero Nuria,Torras Joan,Riera Lluís,Meneghini Maria,Taco Omar,Manonelles Anna,Paul Javier,Seron Daniel,Facundo Carme,Cruzado Josep M,Gil Vernet Salvador,Grinyó Josep M,Bestard Oriol Clinical infectious diseases : an official publication of the Infectious Diseases Society of America BACKGROUND:Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies. METHODS:This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γ release assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)-specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. RESULTS:Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30-9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31-59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89-237.96]). CONCLUSIONS:Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell-depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation. CLINICAL TRIALS REGISTRATION:NCT02550639. 10.1093/cid/ciz1209
    External Validation of the DynPG for Kidney Transplant Recipients. Lenain Rémi,Dantan Etienne,Giral Magali,Foucher Yohann,Asar Özgür,Naesens Maarten,Hazzan Marc,Fournier Marie-Cécile Transplantation BACKGROUND:In kidney transplantation, dynamic prediction of patient and kidney graft survival (DynPG) may help to promote therapeutic alliance by delivering personalized evidence-based information about long-term graft survival for kidney transplant recipients. The objective of the current study is to externally validate the DynPG. METHODS:Based on 6 baseline variables, the DynPG can be updated with any new serum creatinine measure available during the follow-up. From an external validation sample of 1637 kidney recipients with a functioning graft at 1-year posttransplantation from 2 European transplantation centers, we assessed the prognostic performance of the DynPG. RESULTS:As one can expect from an external validation sample, differences in several recipient, donor, and transplantation characteristics compared to the learning sample were observed. Patients were mainly transplanted from deceased donors (91.6% versus 84.8%, p<0.01), were less immunized against HLA class I (18.4% versus 32.7%, p<0.01) and presented less comorbidities (62.2% for hypertension versus 82.7%, p<0.01; 25.1% for cardiovascular disease versus 33.9%, p<0.01). Despite these noteworthy differences, the AUC varied from 0.70 (95%CI from 0.64 to 0.76) to 0.76 (95%CI from 0.64 to 0.88) for prediction times at 1 and 6 years posttransplantation respectively, and calibration plots revealed reasonably accurate predictions. CONCLUSION:We validated the prognostic capacities of the DynPG in terms of both discrimination and calibration. Our study showed the robustness of the DynPG for informing both the patient and the physician, and its transportability for a cohort presenting different features than the one used for the DynPG development. 10.1097/TP.0000000000003209