Search

Purpose of Review: Discuss the recent evidence on cytomegalovirus (CMV) serology in allogeneic hematopoeic cell transplant (HCT) recipients., Recent Findings: Whereas the role CMV-specific cellular mediated immunity has recently emerged as an important factor of CMV DNAemia posttransplant, the value of CMV serology has remained unchanged through decades, associated with donor selection and posttransplant prophylactic and monitoring strategies. In this review, we describe and discuss the emerging reports on the association between the magnitude of pretransplant CMV immunoglobulin G (IgG) titer and the posttransplant incidence of CMV DNAemia, as CMV IgG titer could become an additional tool in CMV risk assessment in the future., Summary: Pretransplant recipient CMV serology may have significant implications in posttransplant CMV reactivation in allogeneic HCT recipients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Biological markers of stress have been associated with HIV progression and pathogenesis but not with HIV incidence. We sought to determine if elevated stress-responsive biomarkers would be associated with incident HIV among adolescent girls and young women (AGYW)., Design: We conducted a case-cohort study within the HIV Prevention Trials Network (HPTN) 068 study among 949 AGYW in South Africa. Cases were AGYW who tested HIV-positive during the eight-year follow-up. Unmatched controls were randomly selected from the HIV-negative population at enrollment., Methods: Dried blood spots from cases and controls were tested from enrollment (2011-2012) for C-reactive protein (CRP), herpes simplex virus type-1 (HSV-1) antibody titers, and cytomegalovirus (CMV) antibody titers. Cox proportional hazards models estimated the association between each biomarker and time to incident HIV., Results: Compared to AGYW with the lowest CRP levels, those with medium and high CRP levels had a higher hazard ratio (HR) of incident HIV [HR: 1.45, 95% confidence interval (CI): 0.95, 2.21; HR: 1.50, 95% CI: 0.98, 2.30, respectively], although not statistically significant. The relative hazard of incident HIV was also higher among AGYW who were CMV seropositive vs. seronegative (low antibodies HR: 2.18, 95% CI: 1.2, 3.87; medium HR: 2.25, 95% CI: 1.28, 3.95; high HR: 1.78, 95% CI: 0.99, 3.21). Those with the highest HSV-1 antibody levels experienced an increased hazard of HIV compared to those who were HSV-1 seronegative (HR: 1.58, 95% CI: 1.03, 2.44)., Conclusions: Biological stress may increase AGYW's susceptibility to HIV acquisition through changes in immune function, viral infection, and increased biological vulnerability to disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Lower socioeconomic status (SES) can accelerate immune aging; however, it is unknown whether and how lifespan socioeconomic context (SEC)-the relative wealth and quality of the communities an individual lives in across their lifespan-impacts immune aging. We examined the effects of childhood and adulthood SEC on late-differentiated immune cells and investigated the mediating and moderating role of cytomegalovirus (CMV), a key driver of immune aging., Methods: Adults 60 years and older ( N = 109) reported their addresses from birth to age 60 years, which were coded for county-level employment, education, and income to construct a latent SEC variable, averaged across ages 0 to 18 years (childhood SEC) and 19 to 60 years (adulthood SEC). Blood was drawn semiannually for 5 years for CMV serostatus and flow cytometry estimates of late-differentiated CD8 + T and natural killer cells. Models were adjusted for chronological age, time, sex, and individual SES (current income and education)., Results: Lower childhood SEC was associated with higher percentages of late-differentiated CD8 + T and natural killer cells via CMV seropositivity (indirect effects, p values = .015-.028). In addition, an interaction between CMV serostatus and SEC on CD8 + T-cell aging ( p = .049) demonstrated that adulthood SEC was negatively associated with immune aging among CMV- but not CMV+ adults., Conclusions: Beyond current SES, SEC related to immune aging in distinct patterns by lifespan phase. Lower childhood SEC importantly may influence who acquires CMV, which in turn predicts higher levels of immune aging, whereas higher adulthood SEC was protective against immune aging among CMV- older adults. These initial results need to be explored in larger samples., (Copyright © 2023 by the American Psychosomatic Society.)

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with hematologic diseases but is associated with high mortality and morbidity. Cytomegalovirus (CMV) infection is common in HSCT patients and modulates vitamin D metabolism in vitro. We aimed at validating CMV-associated vitamin D metabolism in vivo in HSCT., Methods: Patients treated for significant CMV viremia after HSCT were evaluated for CMV load before, during, and after antiviral treatment. RNA was isolated from whole-blood samples to test for regulation of key components of the vitamin D receptor (VDR) pathway during different phases of CMV viremia., Results: CMV viremia developed a mean time of 102 (±34) d post-HSCT. Maximum levels of CMV-DNA reached a mean of 5668 (±7257) copies/mL. VDR expression was downregulated to a mean of 64.3% (±42.5%) relative to the VDR expression pre-CMV viremia (P = 0.035) and lagged in recovery following antiviral treatment. Toll-like receptor (TLR) 2 mRNA was upregulated to 225.4% during CMV viremia relative to the expression pre-CMV viremia (P = 0.012) but not TLR6/7/8 and the TLR-adaptor protein MyD88. Levels of 25-OH vitamin D were reduced in all viremic patients (48.0 ± 4.8 versus 25.1 ± 3.7 ng/mL) and were even lower after periods of CMV viremia compared with the control group (48.3 ± 3.5 versus 17.8 ± 1.8 ng/mL; P = 0.008)., Conclusions: CMV viremia is associated with significant dysregulation of vitamin D metabolism in HSCT patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

[Figure: see text].

Background: Previous studies on the association between cytomegalovirus (CMV) infection and cardiac allograft vasculopathy (CAV) were conducted on patients transplanted in the prevalganciclovir prophylaxis era. The aim of our study is to evaluate this relation in heart transplantation (HTx) recipients treated according to current prophylactic and immunosuppressive regimens., Methods: This single-center retrospective study included all consecutive adult patients that underwent HTx between January 1, 2000, and May 31, 2018. Clinically relevant CMV infection was defined as either plasma CMV DNAemia ≥ 1000 IU/mL with/without clinical symptoms or <1000 IU/mL with symptoms. The primary endpoint was first manifestation of CAV diagnosed by coronary angiography. For statistical analysis, the cause-specific hazard regression model was applied, with clinically relevant CMV infection and any CMV infection as time-dependent variables., Results: In total, 260 patients were included in the analysis. The median (interquartile range) follow-up was 7.88 (4.21-12.04) years. During the follow-up, clinically relevant CMV infection was diagnosed in 96 (37%) patients and CAV in 149 (57%) patients. In the multivariate regression analysis, independent predictors of CAV were: number of rejection episodes (cause-specific hazard ratio [95% confidence interval]: 1.18 [1.04-1.34], P = 0.01), hypertension (1.61 [1.11-2.34], P = 0.01), treatment with mycophenolate mofetil (0.68 [0.47-0.97], P = 0.03). No significant association was observed between CMV infection and CAV, except for patients who experienced a breakthrough CMV infection (n = 24) during prophylaxis (1.94 [1.11-3.40], P = 0.02)., Conclusions: In the era of contemporary immunosuppression and valganciclovir prophylaxis, a significant effect of CMV infection on the risk of CAV was seen only among HTx recipients with CMV breakthrough infection.

Cytomegalovirus (CMV) is a β-herpesvirus that establishes lifelong latency in infected hosts. Following transplantation of a latently infected organ, reactivation can occur and consists of a spectrum of clinically apparent syndromes from mild symptoms to tissue-invasive, resulting in both direct and indirect sequelae. Before the advent of effective antiviral agents, the primary treatment was reduction in immunosuppression (IS). While antiviral agents provide effective prophylaxis, there are several important caveats associated with their use, including drug toxicity and resistance. The traditional view attributes CMV reactivation and the ensuing clinical disease primarily to IS, either intrinsic to disease-related immune compromise or from the extrinsic administration of IS agents. However, previous data from both animal models and human subjects showed that inflammatory signals could induce upregulation of latent viral gene expression. New data demonstrate that ischemia/reperfusion is necessary and sufficient to induce CMV reactivation following murine transplantation of a latently infected graft. In this article, we review a growing body of evidence that suggests that reactivation of both human CMV and murine CMV is first triggered by molecular events that activate CMV gene expression and lytic infection and viral dissemination are then facilitated by IS. The initial activation of viral gene expression may be mediated by oxidative stress, DNA damage, or inflammatory cytokines, and these factors may act synergistically. New therapeutic approaches are needed to capture this complex array of targets.

: The use of cytomegalovirus (CMV) as a vaccine vector to express antigens against multiple infectious diseases, including simian immunodeficiency virus, Ebola virus, plasmodium, and mycobacterium tuberculosis, in rhesus macaques has generated extraordinary levels of protective immunity against subsequent pathogenic challenge. Moreover, the mechanisms of immune protection have altered paradigms about viral vector-mediated immunity against ectopically expressed vaccine antigens. Further optimization of CMV-vectored vaccines, particularly as this approach moves to human clinical trials will be augmented by a more complete understanding of how CMV engenders mechanisms of immune protection. This review summarizes the particulars of the specific CMV vaccine vector that has been used to date (rhesus CMV strain 68-1) in relation to CMV natural history.

Background: Cytomegalovirus (CMV)-infection remains a major cause of morbidity and mortality after lung transplantation. Treatment with currently available drugs poses treatment difficulties in some patients due to drug resistance or intolerability., Methods: We report a series of 4 lung transplant recipients with CMV-infection and treatment failure upon standard care due to antiviral drug resistance and treatment-limiting side effects. As rescue therapy letermovir recently approved for the prophylaxis of CMV-infection in patients after hematopoietic stem cell transplantation was initiated. Patients received 480 mg/day for a follow up of 36.1 ± 12.9 weeks. Efficacy and tolerability were assessed retrospectively., Results: Mild nausea, vomiting, and diarrhea were the only side effects of letermovir reported by a single patient. A small adjustment of the tacrolimus dose was mandatory upon treatment initiation with letermovir. CMV viral load could be decreased and cleared subsequently in all patients. CMV clearance was observed after 17.7 ± 12.6 weeks despite lack of CMV-immunity., Conclusions: CMV-infection and -disease were successfully managed with letermovir. Letermovir was well tolerated and effective in treating CMV-infections in lung transplant recipients failing on currently available antiviral agents.

Background: Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution., Methods: Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction., Results: Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir., Conclusions: We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.

Background: To evaluate if splenectomy results in severely impaired immune responses against primary cytomegalovirus (CMV) infection compared to the general immunocompetent population., Methods: We performed a systemic literature review to study CMV infections in splenectomized individuals, a special population group presently considered immunocompetent to viral infections. We retrieved 30 cases with established CMV infection post-splenectomy and we recorded their disease manifestations, laboratory findings, immunological studies, and histopathology reports. In addition, we retrieved numerous multidisciplinary articles in view of post-splenectomy immunology defects, as well as of immune responses to primary invading CMV in the absence of the spleen. Two clinical studies directly comparing splenectomized with nonsplenectomized individuals under severe iatrogenic immunosuppression as well as the numerically largest review articles of CMV infections in immunocompetent were retained., Results: Splenectomy results in the loss of spleen's ability to fend-off blood-borne pathogens and impairs the link between innate and adaptive immunity. The major post-splenectomy immune-defects against CMV are: weakened, delayed or absent anti-CMV IgM, and compensatory marked IgG response; severely impaired B-cell and CD4, CD8 T-cells function responses; and post-splenectomy, bone marrow compensates for the absence of spleen's immune responses against CMV, mimicking a monoclonal T-cell lymphoproliferative process., Conclusion: The puzzled diagnosis of the CMV syndrome post-splenectomy is of the most challenging and misleading, resulting in risky and costly interventions and a subsequent prolonged hospitalization (2 months). The mounting multi-disciplinary literature evidence renders us to suggest that splenectomized individuals are not only prone to encapsulated bacteria but also behave as immunocompromised to CMV.

Background: In lung transplant recipients, immunosuppressive medications result in impaired antiviral immunity and a propensity for cytomegalovirus (CMV) reactivation within the lung allograft. Natural killer (NK) cells play a key role in immunity to CMV, with an increase in the proportion of NK cells expressing activating CD94-NKG2C receptors in the blood being a strong correlate of CMV infection. Whether a similar increase in NKG2C NK cells occurs in lung transplant recipients following CMV reactivation in the allograft and if such cells contribute to viral control remains unclear., Methods: In this pilot study, we longitudinally assessed the frequency and phenotype of NKG2C NK cells in the blood and bronchoalveolar lavage (BAL) of lung transplant recipients and stratified recipients based on their risk of developing CMV disease., Results: We observed an increase in the proportion of NKG2C NK cells in the blood and BAL of CMV high-risk patients, coincident with both the cessation of antiviral prophylaxis and subsequent detection of actively replicating CMV in the blood and lung allograft. Additionally, these NKG2C NK cells expressed killer-cell immunoglobulin-like receptors distinct from those of other NK subsets and BAL NKG2C NK cells possessed an activated phenotype. Finally, the frequency of NKG2C NK cells in the BAL may be inversely correlated with CMV blood titers., Conclusions: Monitoring the phenotype of NK cells postlung transplant may be a useful biomarker for monitoring patient levels of CMV immunity.

Objectives: CD8 T cells recognize human leukocyte antigen-peptide complex through the T-cell receptor. Although amino acid variation in T-cell receptor variable chains often affects antigen specificity, dimorphism in the beta chain constant region (TRBC1 and TRBC2) is not thought to affect T-cell function. A recent study suggested that adoptive transfer of TRBC1-specific chimeric antigen-receptor-T cells provided an option for T-cell leukemia therapy that preserved T-cell immunity in the TRBC2 subset. This raises an important question as to whether TRBC1T cells are qualitatively different from TRBC2T cells., Design: Cross-sectional study., Methods: Sixty-six antiretroviral therapy-naive HIV-infected individuals, including 19 viraemic controllers and 47 noncontrollers, were enrolled. Peripheral blood mononuclear cells were isolated for T-cell functional assays, tetramer analyses, TRBC1 staining and immunophenotyping., Results: Viraemic controllers had a higher proportion of circulating TRBC1T cells than noncontrollers, raising the possibility that TRBC1T cells might be associated with HIV control. TRBC1T cells also showed more functional T-cell responses against both HIV and cytomegalovirus (P < 0.01). The immunophenotypes of TRBC1-bearing T cells were skewed towards naive and central memory phenotypes, whereas the majority of TRBC2-expressing T cells were terminally differentiated. Inverse correlations were observed between %TRBC1T cells and HIV plasma viral load, which was most pronounced for CD8 T cells (r = -0.7096, P = 0.00002357)., Conclusion: These data suggest that TRBC1T-cell responses are of better quality than their TRBC2 counterparts, which should be considered in immunotherapeutic strategies for HIV infection. Conversely, depletion of TRBC1T cells as part of the treatment of TRBC1 T-cell malignancies may lead to compromised T-cell response quality.

Background: Cytomegalovirus (CMV) is a common viral pathogen in transplant patients which often targets the stomach. However, the endoscopic characteristics of gastric CMV infection are not well established. We aimed to develop a predictive model using endoscopic findings for gastric CMV infection in renal transplant patients., Methods: A retrospective study of 287 kidney transplant recipients who underwent endoscopy with biopsy for suspected CMV infection from January 2006 to November 2015 at a tertiary referral hospital was performed. CMV infection was defined based on inclusion bodies in hematoxylin and eosin and immunohistochemical staining. Endoscopic and clinical parameters related to gastric CMV infection were selected by univariate analyses. Multivariate logistic regression was used to create a predictive model from β-coefficients., Results: CMV was present in 107 (37.7%) of the 287 patients. Multivariate analysis found age (odds ratio [OR], 0.964; 95% confidence interval [CI], 0.938-0.99; P = 0.008), erosions with surface exudate (OR, 5.34; 95% CI, 2.687-10.612; P < 0.001), raised shape of erosions (OR, 3.957; 95% CI, 1.937-8.083; P < 0.001), and antral location of ulcers (OR, 15.018; 95% CI, 5.728-39.371; P < 0.001) as independent predictive factors for gastric CMV infection. Using the predictive model created from this analysis, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71.03%, 85.56%, 74.51%, 83.24%, and 80.14%, respectively. The area under the receiver operating characteristic curve of this model for detecting CMV infection was 0.850 (95% CI, 0.803-0.889; P < 0.001)., Conclusions: The predictive model with typical endoscopic findings may be useful for detecting gastric CMV infection in renal transplant patients.

Background: We provide the results of the first interventional study of cytomegalovirus (CMV)-specific immune monitoring to direct the length of antiviral prophylaxis in lung transplantation (LTx)., Methods: Patients (n = 118) at risk of CMV infection were randomized 1:2 to either 5 months or variable length valganciclovir prophylaxis (5-11 mo post-LTx), as determined by the QuantiFERON (QFN)-CMV assay. Patients with a negative QFN-CMV assay (< 0.2 IU/mL) received prolonged valganciclovir prophylaxis., Results: The primary endpoint that was the incidence of CMV infection in the lung allograft within 18 months of LTx was significantly reduced in the QFN-CMV directed arm (37% versus 58%, P = 0.03). Secondary endpoints that included blood viremia, acute rejection, and chronic lung allograft dysfunction did not differ between the 2 arms. Of the 80/118 patients who ceased antiviral prophylaxis at 5 months, the incidence of viremia (> 600 copies/mL) within the blood was significantly reduced in patients with a positive QFN-CMV assay compared with those without protective immunity (13% versus 67%, P = 0.0003), as was the incidence of severe viremia (> 10 000 copies/mL) (3% versus 50%, P < 0.001). Ceasing antiviral prophylaxis at 11 months in patients with a negative assay was associated with a 25% incidence of late CMV viremia., Conclusions: Cytomegalovirus immune monitoring allows an individualized approach to CMV prophylaxis and reduces late CMV infection within the lung allograft.

Background: Control of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) requires a functional immune system. We assessed the association between quantitation and function of CMV-specific CD8+ T cells and CMV infection in SOT recipients., Methods: During a 10-year period, selected kidney, heart, lung, pancreas, liver, and composite tissue recipients were tested for CMV-specific CD8+ T cells immune competence (CMV-CD8+), as measured by enumeration, interferon-gamma production, and CD107a/b degranulation. Quantitative and functional data were used to assemble T-cell immune competence (TIC) score. CMV infection was diagnosed by polymerase chain reaction in blood and other samples or histopathology., Results: Of 130 patients tested, 59 had CMV infection or disease. The median onset to CMV infection was 10.5 months (interquartile range [IQR], 5.5-18.7). Gastrointestinal disease (28.8%), pneumonia (20.3%), and CMV syndrome (17%) were most common presentation. An impaired nonspecific or CMV-CD8+ TIC score was associated with tissue-invasive disease (hazard risk, 2.84, 95% confidence interval, 1.03-11.81; P = 0.04). Patients with impaired CMV-CD8+ TIC score had longer viremia duration (42.4 days vs 18.8 d; P < 0.001). Patients with impaired nonspecific or CMV-CD8+ TIC score had higher risk of relapse (68.8% vs 27.9%; hazard risk, 2.56; 95% confidence interval, 1.09-5.89; P = 0.03). Patients with CMV infection or disease had lower median absolute lymphocyte count (380 [IQR, 240-540] vs 940 [IQR, 551-1210] cells/mm; P < 0.0001) and CD4+ T cell count (29 cells/mm [IQR, 1.3-116.0] vs 325.5 cells/mm [IQR, 151.5-589.8]; P < 0.0001)., Conclusions: Nonspecific and CMV-specific CD8+ T-cell function correlated with the course of CMV after SOT, and measuring these has the potential to assist in its clinical management.

Purpose of Review: CMV-vectored vaccines expressing SIV antigens have mediated unprecedented levels of virus control following SIV challenge in rhesus macaques. Remarkably, protection was dependent on nonclassically restricted CD8 T cells. Here, we review the latest research in CMV-vectored vaccines in both humans and nonhuman primates as well as recent advances in the understanding nonclassically restricted T cells, particularly MHC-E-restricted CD8 T cells., Recent Findings: Recent studies have investigated human translation of CMV-vectored vaccines including studies to ensure vaccine vector safety. Other work has focused on testing of animal models to investigate the relative contribution of MHC diversity and CMV strain on T-cell induction. Lastly, several groups have investigated MHC-E peptide binding, including HLA-E, have found that MHC-E can accommodate different peptide motifs, consistent with the original observations in CMV-vaccinated macaques., Summary: CMV remains a promising vaccine vector with the potential to be protective against multiple diseases, including HIV. However, CMV is highly species-specific and in humans, congenital infection can lead to serious birth defects. To ensure safe translation to humans, further clinical and animal studies are needed to better understand CMV-vectored immunity as well as more basic immunological questions relating to the induction of classical vs. nonclassical T cells.

Background: Whether cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) at prophylaxis cessation predicts D+/R+ kidney transplants at risk of late-onset CMV infection after receiving distinct induction therapies is still not well characterized., Methods: We prospectively assessed CMV-specific CMI predicting late-onset CMV infection at prophylaxis withdrawal and at earlier time-points, in 96 consecutive D+/R+ patients receiving either anti-interleukin 2-receptor antibody (anti-IL2RA; n = 50) or rabbit antithymoglobulin (n = 46). CMV-specific CMI was evaluated against CMV antigens (IE-1, pp65) using an IFN-γ ELISpot assay., Results: Fourteen (14.6%) of 96 patients developed late-onset CMV infection and 2 (2.1%) of 96 displayed disease. At 3 months, CMV-specific CMI frequencies were significantly lower in patients developing late-onset CMV infection (P < 0.001 for IE-1, P = 0.030 for pp65), regardless the type of induction therapy. Receiver operating characteristic curve analyses showed accurate CMV-specific CMI cutoffs (25 and 130 IFN-γ spots for IE-1 and pp65, respectively) classifying patients into high risk, intermediate risk, or low risk (log-rank = 0.006; hazard ratio, 4.084; 95% confidence interval, 1.431-11.651; P = 0.009), being IE-1 CMI the strongest predictor (odds ratio, 5.554; 95% confidence interval, 1.486-20.766; P = 0.011). Although the profound posttransplant CMV-specific CMI inhibition among rabbit antithymocyte globulin-treated patients precludes its use for risk stratification both before and early after kidney transplant, a similar proportion of at-risk patients could be identified before month 3 within anti-interleukin 2-receptor antibody-treated patients., Conclusions: Monitoring CMV-specific CMI at 3-month prophylaxis cessation discriminates kidney transplant recipient at risk of late-onset CMV infection, regardless the type of induction therapy.

Objectives: This study aimed to investigate the anti-human cytomegalovirus (CMV) activity of milk from seropositive and seronegative mothers of preterm infants and to analyze its changes throughout the different stages of lactation and after Holder pasteurization, a procedure adopted by donor human milk banks., Methods: Eighteen mothers of preterm infants were enrolled in the study. Colostrum, transitional milk, and mature milk samples were collected and tested for anti-CMV activity. Depletion of immunoglobulins A from milk samples was carried out by jacalin resin. Pools of milk samples were pasteurized according to Holder technique., Results: All samples were endowed with anti-CMV activity, although to a different extent. In CMV IgG-positive mothers, colostra were significantly more active than the transitional milk and mature milk samples. Moreover, they were more potent than colostra from seronegative mothers. Immunoglobulins A depletion in colostra from IgG-positive mothers resulted in a partial loss of anti-CMV activity. Holder pasteurization significantly reduced the antiviral activity., Conclusions: Human milk is endowed with anti-CMV activity and its potency may vary depending on the stage of lactation and the serological status of the mother. This biological property could partially neutralize CMV particles excreted in the milk of CMV IgG-positive mothers thus reducing the risk of transmitting infectious viruses to the infant.

Background: Cytomegalovirus (CMV) infection is implicated in endothelial dysfunction and graft damage after pediatric heart transplantation. CMV-specific immune responses are thought to be necessary for CMV viral control but there is little data in pediatric heart transplantation., Methods: We studied 28 consecutive pediatric heart transplant recipients for 1 year posttransplant. CMV T-cell expressing IFN-γ, TNF-α, and IL-2 in response to ex vivo stimulation with CMV lysates or peptides were measured. Circulating cytokines were measured in plasma. Generalized Additive Models were applied to the data to model changes of cell population dynamics over time., Results: CMV-specific T cell-mediated responses were impaired in the first 8 weeks posttransplant. During this period, 25% of patients had CMV viremia, of which those with VLs of 10 000 or more CMV deoxyribonucleic acid copies/mL were given ganciclovir. In this group, the frequency of CD4+ and CD8+ T cells producing IFN-γ and the CD8+CD57+ granzyme B+ T-cell population increased at 12 to 24 weeks and remained elevated for the duration of the study., Conclusions: We have shown that CMV viremia is associated with CMV-specific immune responses and increased CD8+CD57+ granzyme B+ cells at 1 year posttransplant; however, early responses were not predictive of impending CMV viremia. It remains to be seen if the early CMV immune response detected is associated with endothelial and allograft damage, in light of previous studies demonstrating increased vasculopathy in pediatric patients with CMV viremia.

Primary Epstein-Barr virus (EBV) infection is common in childhood, and dual positivity of serum EBV IgM and cytomegalovirus (CMV) IgM antibodies occur in some cases. This study aimed to evaluate the cause of EBV and CMV IgM dual positivity to determine whether it represents a false-positive finding or a true coinfection.A total of 494 children diagnosed with primary EBV infection, manifesting as infectious mononucleosis, were recruited. The diagnosis was based on positive EBV viral capsid antigen (VCA) IgM antibodies, and serum CMV IgM antibodies and liver enzymes were also evaluated in 149 subjects.Of 149 children with primary EBV infection, 40 (26.8%) had serum EBV VCA IgM and CMV IgM dual positivity. However, true CMV infection was confirmed only in 1 child of 40 (2.5%) who was positive for both serum CMV Ag and urine CMV polymerase chain reaction (PCR) and negative for serum CMV IgG antibody. Among the children with primary EBV infection, the rate of dual positivity was higher in infants and lower in adolescents (P = .013). Liver enzymes were more significantly elevated in children with dual positivity than in those with negative results for CMV IgM antibodies (P = .026), which correlated with the serum EBV and CMV IgM titers.Serum EBV and CMV IgM dual positivity are more prevalent in children with primary EBV infection than what was previously reported. Our results indicate that serum EBV and CMV IgM dual positivity represents a false-positive finding, as opposed to an actual CMV coinfection, possibly due to antigenic cross-reactivity.

Purpose of Review: Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic haematopoietic stem cell transplantation (HSCT). CMV surveillance-preemptive therapy is the current preferred approach for preventing CMV disease after HSCT. In contrast, antiviral prophylaxis is not commonly used due to myelosuppressive effects of valganciclovir. In this article, the role of the newly approved antiviral compound, letermovir, is reviewed., Recent Findings: Letermovir inhibits CMV by interfering viral terminase complex. In a phase 3 randomized placebo-controlled clinical study that enrolled 495 CMV-seropositive HSCT recipients, the primary end point of clinically significant CMV infection was significantly reduced by letermovir prophylaxis. Letermovir was well tolerated without risk of myelotoxicity and nephrotoxicity. Experimental in-vitro data suggest that letermovir may possess low genetic barrier to resistance. In prophylaxis trials, two breakthrough infections were reported due to selection of CMV UL56 V236M mutation., Summary: Letermovir is an important addition to the current strategies for CMV prevention after allogeneic HSCT. Its favourable efficacy and safety profile re-opens door for antiviral prophylaxis another first-line option, similar to CMV surveillance-preemptive therapy, for preventing CMV in allogeneic HSCT recipients.

Background: Few studies have directly compared preemptive therapy (PET) and antiviral prophylaxis (AP) for prevention of cytomegalovirus (CMV) disease in CMV seropositive (R+) orthotopic liver transplant (OLT) recipients., Methods: We prospectively assessed CMV disease and clinical outcomes among 160 consecutive R+ OLT recipients who received PET (weekly plasma CMV PCR for 3 months, oral valganciclovir 900 mg twice daily for CMV viremia >250 IU/mL, until 2 consecutive negative weekly PCR results) and compared them with a historical cohort of 156 R+ recipients who received AP (valganciclovir, 900 mg daily for 3 months)., Results: Patient characteristics were similar between PET and AP cohorts (P > 0.05 all comparisons). In the PET group, 24% (39/160) developed CMV viremia greater than 250 IU/mL at a median of 42 (range, 7-93) days post-OLT. CMV monitoring adherence in the PET cohort was 85% (1488/1760 required tests) and 86% (30/36) initiated PET within 3 days of the CMV result. By 12 months post-OLT, the incidence of CMV disease, acute allograft rejection, major infection, or death in the PET and AP cohorts was not significantly different: 2% versus 2%, 19% versus 16%, 10.5% versus 10.8%, and 5% versus 8%, respectively (P > 0.05 all comparisons). The estimated proportion of drug-exposed patients and average antiviral drug exposure were significantly lower with PET versus AP: 24% versus 100%, P < 0.001, and 15.8 versus 81 g per patient, P < 0.001, respectively., Conclusions: PET is feasible in a nonresearch setting and is associated with similar CMV disease rates and other clinically relevant outcomes to AP in CMV seropositive liver transplant recipients.

Persons with serious mental illness are at high risk for suicide, but this outcome is difficult to predict. Serological markers may help to identify suicide risk. We prospectively assessed 733 persons with a schizophrenia spectrum disorder, 483 with bipolar disorder, and 76 with major depressive disorder for an average of 8.15 years. The initial evaluation consisted of clinical and demographic data as well as a blood samples from which immunoglobulin G antibodies to herpes viruses and Toxoplasma gondii were measured. Suicide was determined using data from the National Death Index. Cox proportional hazard regression models examined the role of baseline variables on suicide outcomes. Suicide was associated with male sex, divorced/separated status, Caucasian race, and elevated levels of antibodies to Cytomegalovirus (CMV). Increasing levels of CMV antibodies were associated with increasing hazard ratios for suicide. The identification of serological variables associated with suicide might provide more personalized methods for suicide prevention.

Background: Urinary CXC chemokine ligand 10 (CXCL10) is a promising biomarker for subclinical tubulointerstitial inflammation, but limited data exist regarding its correlation with (micro)vascular inflammation. Furthermore, no study has evaluated whether concomitant serum CXCL10 improves the discrimination for (micro)vascular inflammation., Methods: We investigated whether serum/urinary CXCL10 reflect subclinical inflammation within different renal compartments. Patients (n = 107) with 107 surveillance biopsies were classified as: normal histology (n = 47), normal histology with polyomavirus BK (BKV) or cytomegalovirus (CMV) viremia (n = 17), moderate-severe tubulointerstitial inflammation (tubulitis ≥2, n = 18), pure microvascular inflammation (n = 15), and isolated v lesions (n = 10). Serum and urinary CXCL10 Enzyme-linked Immunosorbent Assay was performed. An independent validation set was evaluated for urine CXCL10: normal histology (n = 14), normal histology with BKV or CMV viremia (n = 19), tubulitis ≥2 (n = 15), pure microvascular inflammation (n = 41), and isolated v lesions (n = 14)., Results: Elevated urinary CXCL10 reflected inflammation within the tubulointerstitial (urinary CXCL10/creatinine, 1.23 ng/mmol vs 0.46 ng/mmol; P = 0.02; area under the curve, 0.69; P = 0.001) and microvascular compartments (urinary CXCL10/creatinine, 1.72 ng/mmol vs 0.46 ng/mmol; P = 0.03; area under the curve, 0.69; P = 0.02) compared to normal histology. Intriguingly, urinary CXCL10 was predominantly elevated with peritubular capillaritis, but not glomerulitis (P = 0.04). Furthermore, urinary CXCL10 corresponded with BKV, but not CMV viremia (P = 0.02). These urine CXCL10 findings were confirmed in the independent validation set. Finally, serum CXCL10 was elevated with BKV and CMV viremia but was not associated with microvascular or vascular inflammation (P ≥ 0.19)., Conclusions: Urinary CXCL10 reflects subclinical inflammation within the tubulointerstitial and peritubular capillary spaces, but not the vascular/systemic compartments; this was consistent with BKV (tubulointerstitial) and CMV viremia (systemic). Serum CXCL10 was not a useful marker for (micro)vascular inflammation.

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.

Background: Desensitization with IVIG + rituximab combined with alemtuzumab induction gives HLA-sensitized patients an opportunity for successful kidney transplantation. However, it may be associated with a high risk for viral infections due to combined T cell and B cell depletion., Methods: Anti-cytomegalovirus (CMV) activity was assessed in 280 pretransplant and posttransplant blood samples from 33 desensitized patients who received alemtuzumab induction. CMV-specific CD8+ (CMV-Tc), CD4+ (CMV-Th) T cell activity, and natural killer (NK) cell number were measured by flow cytometry. Anti-CMV IgG was measured by enzyme-linked immunosorbent assay, and CMV DNA by polymerase chain reaction., Results: All 30 CMV sero (+) patients were (+) for CMV-Tc and/or Th predesensitization, while 3 sero (-) patients showed no CMV-T cell activity. CMV-Tc and/or Th became (-) in 50% to 70% of these sero (+) patients at 1 month post-alemtuzumab. However, 75% showed CMV-T cell (+) by 2 months and 95% did so by 3 months post-alemtuzumab. More than 50% of pretranslpant NK cell levels were detected post-alemtuzumab. Anti-CMV IgG levels did not decrease posttransplant in sero (+) patients. Four patients developed CMV viremia with clearance by 1.2 months, which correlated with an increase or appearance of CMV-T cells, even in the sero (-) patient., Conclusions: CMV-T cell activity, anti-CMV IgG, and NK cell-mediated antibody-dependent cell cytotoxicity were present in aleumtuzumab-treated CMV sero (+) patients. One sero (-) patient developed CMV-T cell responses post-CMV viremia. These results suggest that the IVIG + rituximab desensitization combined with alemtuzmab induction with triple immunosuppression maintenance does not result in prolonged suppression of anti-CMV immunity or increased risk for CMV infection.

Rationale: Lymphoid interstitial pneumonia (LIP) is a rare disease with lymphocytic infiltration of the alveolar interstitial and air spaces, sometimes classified as a clonal lymphoproliferative disease (LPD) with high prevalence in patients with immunodysregulation. Although association of mucosa-associated lymphoid tissue (MALT) lymphoma development with infectious agents has been well described, it is not so in the case of LIP. Attempts to demonstrate an infective cause by direct microbe detection have failed, but association with atypical specific immune response to opportunistic infectious agent has not been studied., Patient Concerns and Diagnoses: We performed clinical, biochemical, and immunologic analysis of patients LIP that arises primarily from the common variable immune deficiency (CVID) with normal immunoglobulin class M (IgM) level and mild infectious course as a result of immunodysregulation. At the age of 13 multiple nodules, areas of consolidation were observed and LIP was confirmed by histological examination. The progression of the disease with massive splenomegaly (17→27 cm), lymphadenopathy soft tissue infiltration coincides with high standardized uptake value (SUV was 3.1-5.2), regulatory T cells decrease (CD4+25FoxP3+ level -0.02%, i.e., 8 cells per 100 μL), oligoclonal gammapathy: very high IgM (3340 mg/dL) and β2-microglobulin (18.8 mg/L) level observed 10 years later.Immune response polarization was observed in humoral and cellular compartment -Th and Tc-dependent: 10.8% of lymphocytes are CD8high+CMV pp65-pentamer positive cells (Epstein-Barr virus-specific not observed). Specific immune response polarization correlates with negative immunofixation, light chains κ/λ = 2.84 and narrow, but non-monoclonal T cell receptor (TCR)/ B cell receptor (BCR) repertoire., Lessons: Taking everything into account, this case report shows that LIP is a consequence of immune-dysregulation in CVID, that is, Treg deficiency, narrow lymphocyte repertoire, and abnormal ability to respond to cytomegalovirus (CMV) antigens. It may be visualized by positron emission tomography (PET) and monitored by CMV-specific immune response, β2-microglobulin level, and IgM paraproteinaemia, but not by immunofixation and κ/λ ratio.

Background: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling., Methods: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro., Results: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller., Conclusions: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

Characterization of human cytomegalovirus-specific T cells (CMV-T) is of critical importance for their potential use in adoptive immunotherapy after allogeneic hematopoietic stem cell transplantation. Background frequencies of CMV-T in peripheral blood mononuclear cells (PBMCs) of CMV-seropositive healthy subjects are usually very low, hence the requirement for prolonged culture time and multiple stimulations to expand them. The evaluation of the end-culture specificity and composition has sometimes been neglected or difficult to assess in these settings. We explored the identity and the functionality of pp65-specific and IE1-specific T cells, enriched in short-term cultures from PBMCs. Antigen-specific T cells were further isolated by IFN-γ capture system and/or CD154 microbeads. Frequency of IE1-specific cytotoxic T cells in PBMCs secreting IFN-γ was higher compared with the pp65-specific one, whereas the latter cell types showed a higher median CD107a degranulation. Cell viability, rate of CMV-T increase, and multicytokine secretion profile after epitope-specific short-term cultures were heterogenous. T cells were mainly of late effector stages but they significantly dropped off upon CMV rechallenge with peptide pools. In parallel, CMV-T expansion was accompanied by a significant increase of cytotoxic naive/memory stem cells (CTLs), whereas the CD4 counterpart significantly increased only upon stimulation with IE1. Outcome was variable and showed donor and epitope dependency. Differences in human leukocyte antigen and epitope dominance and variability in the relative number of CD3 effector cells and IFN-γ/CD154 expression among healthy donors could reflect the observed individual CMV-specific cellular immunity. This heterogeneity raises points to be considered when approaching adoptive immunotherapy.

Background: Graft-versus-host (GvH) disease (GvHD) remains a serious concern for patients undergoing antiviral cellular therapy. Despite the major improvements in cellular immunotherapy, the immunogenicity of virus-specific T cells has not yet been fully defined. This present study aims to examine how cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTLs) respond to allogeneic antigen stimulation and whether they give rise to GvHD target tissue damage., Methods: Cytomegalovirus-specific CTLs were isolated by the IFN-γ secretion assay (gamma-catch) from healthy seropositive volunteers and expanded in vitro. The levels of intracellular IFN-γ, cytotoxic activity, IFN-γ and granzyme B secretion, and CD25 expression were measured using flow cytometry (fluorescence-activated cell sorting). The ability of CMV-CTLs to induce GvHD target tissue damage was evaluated using the human in vitro skin explant assay (skin explant assay)., Results: Cytomegalovirus-specific CTLs responded specifically to CMV-phosphoprotein 65 stimulation by secreting IFN-γ and killing virus peptide loaded autologous phytohemagglutinin (PHA) blasts. Compared with unselected peripheral blood mononuclear cells, CMV-CTLs induced significantly less severe cutaneous GvH tissue damage. This observation coincided with low levels of CD25 expression, as well as IFN-γ and granzyme B secretion after allogeneic antigen stimulation in both the mixed lymphocyte reaction and in the skin explant assay., Conclusions: Cytomegalovirus-specific CTLs isolated by the IFN-γ secretion assay from HLA-unmatched healthy donors exhibited a high level of anti-CMV potency without inducing significant cutaneous GvH tissue damage in vitro. This finding provides novel evidence supporting the safe use of in vitro expanded CMV-CTLs as an antiviral therapy in transplant patients with refractory CMV infections.

Programmed death-ligand 1 (PD-L1) binds to programmed death-1 (PD-1) on activated T cells and contributes to T-cell exhaustion. PD-L1 expressed on antigen-presenting cells (APCs) could be thought to inhibit the induction of Ag-specific cytotoxic T lymphocytes (CTLs) by transducing negative signal into T cells; however, the roles of PD-L1 on APCs have not yet been well examined. Therefore, we evaluated the roles of PD-L1 on APCs in the induction of Ag-specific CTLs. CD3 T cells isolated from cytomegalovirus (CMV)-seropositive healthy donors were stimulated with mature dendritic cells pulsed with CMV pp65-derived HLA-restricted peptides in the presence of anti-PD-L1 blocking antibody. Unexpectedly, PD-L1 blockade resulted in a less efficient induction of CMV-specific CTLs, suggesting that PD-L1 play a positive role in the induction of Ag-specific CTLs. For further evaluations and application to adoptive immunotherapy, we generated K562-based artificial APCs, which were retrovirally transduced with HLA class I molecules and various combinations of CD80/86 and PD-L1. K562/HLA+CD80/86+PD-L1 cells produced significantly higher induction of CMV-specific CTLs than K562/HLA or K562/HLA+CD80/86 cells without causing excessive differentiation or functional exhaustion of the induced CTLs, whereas PD-L1 itself did not have a stimulatory effect. Furthermore, only K562/HLA+CD80/86+PD-L1 cells pulsed with HLA-A*24:02-restricted Wilms tumor 1 (WT1) peptide clearly expanded WT1-specific CTLs from healthy donors. Our findings presumed that PD-L1 expressed on APCs along with CD80/86 enhanced the induction of Ag-specific CTLs probably depending on fine-tuning excessive stimulation of CD80/86, and that K562/HLA+CD80/86+PD-L1 cells has therapeutic potential as a novel type of artificial APCs for adoptive immunotherapy.

Objective: Socioeconomic disadvantage may contribute to poor health through immune-related biological mechanisms. We examined the associations between socioeconomic status, as measured by annual household income, and T-cell markers of aging, including the ratios of CD4 and CD8 effector cells to naïve cells (E/N ratio) and the CD4/CD8 T-cell ratio. We hypothesized that participants with a lower income would have higher E/N ratios and lower CD4/CD8 ratios compared with participants with a higher income, and that these associations would be partially mediated by elevated cytomegalovirus (CMV) IgG antibody levels, a virus implicated in aging and clonal expansion of T cells., Methods: Data were from 79 individuals who participated in the population-based Detroit Neighborhood Health Study. We used linear regression to quantify the association between a $10,000 decrease in income and each ratio outcome., Results: After adjustment for age, sex, race, smoking, medication use, and lifetime history of mental health conditions, lower income was associated with a 0.41 (95% confidence interval = 0.09-0.72) log-unit increase in the CD4 E/N ratio and a 0.20 (95% confidence interval = 0.02-0.39) log-unit increase in the CD8 E/N ratio. CMV immunoglobulin G antibody level partially mediated these associations., Conclusions: Our study suggests that low socioeconomic status is associated with immunological aging as measured by the E/N ratio and that impaired immune control of CMV may partially mediate these associations.

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.

Cytomegalovirus (CMV) is a highly complex pathogen which, despite modern prophylactic regimens, continues to affect a high proportion of thoracic organ transplant recipients. The symptomatic manifestations of CMV infection are compounded by adverse indirect effects induced by the multiple immunomodulatory actions of CMV. These include a higher risk of acute rejection, cardiac allograft vasculopathy after heart transplantation, and potentially bronchiolitis obliterans syndrome in lung transplant recipients, with a greater propensity for opportunistic secondary infections. Prophylaxis for CMV using antiviral agents (typically oral valganciclovir or intravenous ganciclovir) is now almost universal, at least in high-risk transplants (D+/R-). Even with extended prophylactic regimens, however, challenges remain. The CMV events can still occur despite antiviral prophylaxis, including late-onset infection or recurrent disease, and patients with ganciclovir-resistant CMV infection or who are intolerant to antiviral therapy require alternative strategies. The CMV immunoglobulin (CMVIG) and antiviral agents have complementary modes of action. High-titer CMVIG preparations provide passive CMV-specific immunity but also exert complex immunomodulatory properties which augment the antiviral effect of antiviral agents and offer the potential to suppress the indirect effects of CMV infection. This supplement discusses the available data concerning the immunological and clinical effects of CMVIG after heart or lung transplantation.

Cytomegalovirus (CMV) infection negatively influences both short- and long-term outcomes after cardiothoracic transplantation. In heart transplantation, registry analyses have shown that CMV immunoglobulin (CMVIG) with or without virostatic prophylaxis is associated with a significant reduction in mortality and graft loss versus no prophylaxis, particularly in high-risk donor (D)+/recipient (R)- transplants. Randomized comparative trials are lacking but retrospective data suggest that addition of CMVIG to antiviral prophylaxis may reduce rates of CMV-related events after heart transplantation, including the incidence of acute rejection or chronic allograft vasculopathy. However, available data consistently indicate that when CMVIG is used, it should be administered with concomitant antiviral therapy, and that evidence concerning preemptive management with CMVIG is limited, but promising. In lung transplantation, CMVIG should again only be used with concomitant antiviral therapy. Retrospective studies have shown convincing evidence that addition of CMVIG to antiviral prophylaxis lowers CMV endpoints and mortality. The current balance of evidence suggests that CMVIG prophylaxis reduces the risk of bronchiolitis obliterans syndrome, but a controlled trial is awaited. Overall, the relatively limited current data set suggests that prophylaxis with CMVIG in combination with antiviral therapy appears effective in D+/R- heart transplant patients, whereas in lung transplantation, addition of CMVIG in recipients of a CMV-positive graft may offer an advantage in terms of CMV infection and disease.

Intravenous ganciclovir and, increasingly, oral valganciclovir are now considered the mainstay of treatment for cytomegalovirus (CMV) infection or CMV disease. Under certain circumstances, CMV immunoglobulin (CMVIG) may be an appropriate addition or, indeed, alternative. Data on monotherapy with CMVIG are limited, but encouraging, for example in cases of ganciclovir intolerance. In cases of recurrent CMV in thoracic transplant patients after a disease- and drug-free period, adjunctive CMVIG can be considered in patients with hypogammaglobulinemia. Antiviral-resistant CMV, which is more common among thoracic organ recipients than in other types of transplant, can be an indication for introduction of CMVIG, particularly in view of the toxicity associated with other options, such as foscarnet. Due to a lack of controlled trials, decision-making is based on clinical experience. In the absence of a robust evidence base, it seems reasonable to consider the use of CMVIG to treat CMV in adult or pediatric thoracic transplant patients with ganciclovir-resistant infection, or in serious or complicated cases. The latter can potentially include (i) treatment of severe clinical manifestations, such as pneumonitis or eye complications; (ii) patients with a positive biopsy in end organs, such as the lung or stomach; (iii) symptomatic cases with rising polymerase chain reaction values (for example, higher than 5.0 log10) despite antiviral treatment; (iv) CMV disease or CMV infection or risk factors, such as CMV-IgG-negative serostatus; (vi) ganciclovir intolerance; (vii) patients with hypogammaglobulinemia.

Rationale: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals., Objective: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients., Methods and Results: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/μL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001)., Conclusions: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wolters Kluwer.)

Background: The role of CTLA4 gene polymorphisms in T-cell-mediated immunity in association with human cytomegalovirus (HCMV) infection after transplantation is poorly understood. In the present study, we have made an attempt to investigate the impact of CTLA4 single nucleotide polymorphisms (SNPs) (rs231775, rs5742909, rs11571317, rs16840252, rs4553808, rs3087243) and dinucleotide (AT)n repeat polymorphism on the incidence of symptomatic HCMV infection (disease) among 270 renal allograft recipients., Materials and Methods: Genotyping of CTLA4 SNPs was performed by a PCR, followed by a restriction fragment length polymorphism assay. The detection of the dinucleotide (AT)n repeat polymorphism was carried out by PCR-polyacrylamide gel electrophoresis., Results: An almost three-fold increased risk was observed for the incidence of symptomatic HCMV infection in mutant genotype carriers of rs231775 and rs3087243 SNPs under additive and recessive models, respectively. The mutant haplotype carriers of six studied SNPs (rs231775, rs5742909, rs11571317, rs16840252, rs4553808 and rs3087243) showed an almost two-fold higher risk for symptomatic HCMV cases, whereas wild-type haplotype combinations of these six SNPs showed a protective effect. Subsequently, no correlation was observed in the promoter region SNPs of CTLA4, namely, rs5742909, rs11571317, rs16840252 and rs4553808 in symptomatic HCMV cases at the genotypic/allelic level. Survival analysis showed that the mutant genotypes of rs231775 and rs3087243 SNPs were associated with the lowest HCMV disease-free survival compared with heterozygous and wild genotypes. The crude and adjusted hazard ratios showed an almost three-fold and 2.5-fold increased risk in univariate and multivariate Cox regression models, respectively, for HCMV disease-free survival against mutant genotypes of rs231775 and rs3087243 SNPs. CTLA4 dinucleotide (AT)n repeat analysis showed that the smaller allele (102 bp) was associated with a protective effect, whereas the longer (110 and 116 bp) alleles showed a susceptible effect for symptomatic HCMV cases., Conclusion: These results suggested that CTLA4 variants might be involved in the clinical manifestation of HCMV diseases.

Background: Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients., Methods: The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA-loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval., Results: De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial., Conclusion: In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts.

Purpose of Review: To consider new treatment options for cytomegalovirus (CMV) infection, review recent trials, and anticipate their use in clinical practice, focussing on bone marrow transplantation, congenital infection, and intervention during pregnancy., Recent Findings: Three double-blind randomized placebo-controlled phase 2 proof-of-concept studies have each identified a novel antiviral drug with activity against CMV infection in bone marrow transplant patients. One of these (brincidofovir) inhibits the DNA polymerase that is the target of the currently licensed drug ganciclovir. Another new drug (maribavir) inhibits a protein kinase which, coincidentally, is the enzyme responsible for activating ganciclovir through phosphorylation. The third drug (letermovir) inhibits the terminase enzyme complex responsible for packaging unit length DNA into assembling virions.In addition, in a double-blind randomized placebo-controlled trial in neonates with symptomatic congenital CMV infection, a 6-month course of valganciclovir was superior to the standard 6-week course of the same drug. In pregnant women with primary CMV infection, administration of hyperimmune immunoglobulin did not significantly reduce transmission of CMV across the placenta., Summary: The ability to diagnose CMV infections reliably in different clinical settings through application of molecular laboratory methods has ushered in new ways of evaluating potential new treatments for CMV. Several of these may help control the diseases caused by this important human pathogen.

Background: Cytomegalovirus (CMV) disease occurs in 16% to 20% of low-risk, CMV-positive renal transplant recipients. The cutoffs for quantitative real-time polymerase chain reaction (qPCR) or phosphoprotein (pp65) antigenemia (pp65emia) for starting preemptive therapy have not been well established., Methods: We measured qPCR and pp65emia weekly from day 7 to day 120 after transplantation, in anti-CMV immunoglobulin G–positive donor and recipient pairs. Patients and physicians were blinded to the test results. Suspicion of CMV disease led to the order of new tests. In asymptomatic viremic patients, the highest pp65emia and qPCR values were used, whereas we considered the last value before diagnosis in those with CMV disease., Results: We collected a total of 1,481 blood samples from 102 adult patients. Seventeen patients developed CMV disease, 54 presented at least one episode of viremia that cleared spontaneously, and 31 never presented viremia. Five patients developed CMV disease after the end of the study period. The median (95% confidence interval) pp65emia and qPCR values were higher before CMV disease than during asymptomatic viremia (6 [9–82] vs. 3 [1–14] cells/10(6) cells; P<0.001 and 3,080 [1,263–15,605] vs. 258 [258–1,679] copies/mL; P=0.008, respectively). The receiver operating characteristic curve showed that pp65emia 4 cells/10(6) cells or greater showed a sensitivity and specificity to predict CMV disease of 69% and 81%, respectively (area, 0.769; P=0.001), with a positive predictive value of 37% and a negative predictive value of 93%. For qPCR 2,000 copies/mL or higher, the positive predictive value and negative predictive value were 57% and 91%, respectively (receiver operating characteristic area, 0.782; P=0.000)., Conclusion: With these cutoffs, both methods are appropriate for detecting CMV disease.

Objective: Low CD4/CD8 T-cell ratios occur in conditions associated with reduced immune resilience, including older age and HIV infection. Effective antiretroviral therapy increases CD4/CD8 T-cell ratios, but often not to preinfection levels. The reasons for this deficit remain unclear. As cytomegalovirus (CMV) infection exacerbates falling CD4/CD8 T-cell ratios and immune senescence in the old elderly population, we investigated whether CMV infection is associated with refractory inversion of CD4/CD8 T-cell ratios and increased phenotypic evidence of immune senescence in HIV infection., Design: An observational cohort study of HIV-infected individuals attending the Newfoundland and Labrador Provincial HIV Clinic in St. John's., Methods: CMV infection status was determined by ELISA with infected cell lysate. Expression of CD28 and CD57 on CD8 T cells and cellular immune responses against CMV were measured by flow cytometry. We compared CD4/CD8 T-cell ratios, percentage of CD8 T cells expressing CD28 and percentage of CD8 T cells expressing CD57 between groups of HIV-infected persons discordant for CMV infection., Results: The CMV-seronegative group had significantly higher CD4/CD8 T-cell ratios, more frequent normalization of the ratio to at least 1, and lesser phenotypic evidence of immune senescence., Conclusion: CMV infection is associated with reduced immune reconstitution in HIV infection, even with suppression of HIV replication below detectable levels. This suggests that CMV infection, or some related factor, influences immune resilience in the setting of HIV infection.

Objective: Despite the strong correlation of T-cell CD38 expression with HIV disease progression, evidence linking CD38 expression and dysfunction at the single cell level is scant. Since CD38⁺ memory CD4⁺ T cells, especially those from HIV-infected persons, fail to induce CD154 (CD40L) while responding to a superantigen with interferon (IFN)-γ or interleukin (IL)-2, we aimed to determine if recall responses to cytomegalovirus (CMV) were similarly affected in the CD38⁺ memory CD4⁺ T-cell subpopulation., Design and Methods: Peripheral blood mononuclear cells from HIV+ patients and healthy controls were incubated 14 h with CMV antigens, the superantigen Staphylococcus aureus enterotoxin B or medium, and labeled for identification of central memory (T(CM)) and effector memory (T(EM)) CD4⁺ T cells, and for the intracellular detection of induced CD154, IFN-γ and/or IL-2 by flow cytometry., Results: Compared with CD38⁻ cells, CD38⁺ T(CM) cells from patients had less CD40L induction after CMV stimulation, and increased IFN-γ response. Patients' CD38⁺ T(EM) cells showed a lower IL-2 response, and tended to have a greater IFN-γ response, in which CD154 induction frequently failed. CMV-specific responses of patients' CD38⁺ T(CM) and T(EM) cells were dominated by IFN-γ, and almost all IL-2⁺ cells co-expressed IFN-γ. IL-2 responses to the polyclonal activator S. aureus enterotoxin B were also significantly less frequent among CD38⁺ T(CM) and T(EM) cells than in CD38⁻ cells., Conclusion: Patients' CD38⁺ memory CD4⁺T-cell responses to CMV favor the effector cytokine IFN-γ over IL-2, in the context of deficient CD154 induction, which may limit co-stimulation, proliferation and survival.