Latent Cytomegalovirus Infection Research Articles

Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation.

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).

The Impact of Latent Cytomegalovirus Infection on Spontaneous Abortion History and Pregnancy Outcomes in Romanian Pregnant Women.

Serum samples from 806 pregnant women (28.29 ± 4.50 years old) who came for a consultation at the Timisoara Clinical Emergency City Hospital between 2008 and 2010 were tested for anti-CMV IgM/IgG antibodies, and data about demography, obstetrical history, pregnancy complications, birth, and neonate were collected. The data were compared between the groups with and without latent CMV infection, and statistical significance was calculated. We did not find a difference regarding cesarean section (OR = 0.916, p = 0.856), placental abruption (OR = 1.004, p = 1.00), pregnancy-induced hypertension rate (OR = 1.078, p = 1.00), secondary sex ratio (0.882, p = 0.857), APGAR score (p = 0.225), gestational age at birth (p = 0.434), or birth weight (p = 0.365). A borderline significant difference was found regarding the presence of miscarriage history: OR = 8.467, p = 0.051. The presence of latent CMV infection does not affect the likelihood of complications in healthy women. A borderline significantly higher prevalence of miscarriage history was found in women with latent CMV infection.

Single-cell transcriptomic and T cell antigen receptor analysis of human cytomegalovirus (hCMV)-specific memory T cells reveals effectors and pre-effectors of CD8+ - and CD4+ -cytotoxic T cells.

Latent human cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune-compromised individuals. Although T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in hCMV immunity is lacking. Here, in an unbiased manner, we characterized over 8000 hCMV-reactive peripheral memory T cells isolated from seropositive human donors, at a single-cell resolution by analysing their single-cell transcriptomes paired with the T cell antigen receptor (TCR) repertoires. The hCMV-reactive T cells were highly heterogeneous and consisted of different developmental and functional memory T cell subsets such as, long-term memory precursors and effectors, T helper-17, T regulatory cells (TREGs ) and cytotoxic T lymphocytes (CTLs) of both CD4 and CD8 origin. The hCMV-specific TREGs , in addition to being enriched for molecules known for their suppressive functions, showed enrichment for the interferon response signature gene sets. The hCMV-specific CTLs were of two types, the pre-effector- and effector-like. The co-clustering of hCMV-specific CD4-CTLs and CD8-CTLs in both pre-effector as well as effector clusters suggest shared transcriptomic signatures between them. The huge TCR clonal expansion of cytotoxic clusters suggests a dominant role in the protective immune response to CMV. The study uncovers the heterogeneity in the hCMV-specific memory T cells revealing many functional subsets with potential implications in better understanding of hCMV-specific T cell immunity. The data presented can serve as a knowledge base for designing vaccines and therapeutics.

The Impact of Cytomegalovirus Infection on Natural Killer and CD8+ T Cell Phenotype in Multiple Sclerosis.

Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.

Smoking changes adaptive immunity with persistent effects

Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability1–6. However, the variables that drive such differences in cytokine secretion—a crucial component of the host response to immune challenges—remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.

Progression of retinal choroidal neovascularizationby latent human cytomegalovirus infection and immunological signaling among neonatal patients admitted to tertiary care hospital.

Choroidal neovascularization (CNV) is a serious condition that affects the retina, causing partial or complete blindness in people of different ages. While CNV is a common occurrence in various chorioretinopathies, research on its occurrence in neonates is limited. Human cytomegalovirus (HCMV) is a significant health threat to neonates, with a strong association with retinal angiogenesis. However, there has been limited investigation into HCMV-associated CNV progression. In this article, we extensively studied the expression of different inflammatory cytokines and chemokines during latent HCMV-associated retinal neovascularization. Our research found that HCMV-induced CNV progression was significantly prominent in the presence of AT2R-dependent angiogenesis (p < 0.001), whereas in the absence of HCMV, AT1R-dependent CCL-5-mediated angiogenesis was documented. We also observed significant increases in CCL-19, CCL-21 chemokine responses, followed by CCR-7 chemokine receptor activation (p < 0.001) in HCMV-induced CNV patients compared to HCMV non-induced CNV groups. Furthermore, significant changes in predictive chemokine markers of HCMV-induced CNV were positively correlated with HCMV viremia. These immunological alterations ultimately lead to the switching of NFκB canonical and noncanonical pathways, respectively, in HCMV-induced neonatal CNV and HCMV non-induced CNV. This clinical observation presents a novel hypothesis that ocular HCMV latency poses a noteworthy risk factor for the progression of retinal neovascularization through a distinctive immunological signaling pathway. The current study represents the first of its kind to report on this association, which may have significant implications for the clinical management of patients with ocular HCMV.

Immunosenescence and Cytomegalovirus: Exploring Their Connection in the Context of Aging, Health, and Disease.

Aging induces numerous physiological alterations, with immunosenescence emerging as a pivotal factor. This phenomenon has attracted both researchers and clinicians, prompting profound questions about its implications for health and disease. Among the contributing factors, one intriguing actor in this complex interplay is human cytomegalovirus (CMV), a member of the herpesvirus family. Latent CMV infection exerts a profound influence on the aging immune system, potentially contributing to age-related diseases. This review delves into the intricate relationship between immunosenescence and CMV, revealing how chronic viral infection impacts the aging immune landscape. We explore the mechanisms through which CMV can impact both the composition and functionality of immune cell populations and induce shifts in inflammatory profiles with aging. Moreover, we examine the potential role of CMV in pathologies such as cardiovascular diseases, cancer, neurodegenerative disorders, COVID-19, and Long COVID. This review underlines the importance of understanding the complex interplay between immunosenescence and CMV. It offers insights into the pathophysiology of aging and age-associated diseases, as well as COVID-19 outcomes among the elderly. By unraveling the connections between immunosenescence and CMV, we gain a deeper understanding of aging's remarkable journey and the profound role that viral infections play in transforming the human immune system.

Risk Factors for CMV Infection, Including HLA Disparity and Ptcy Transplant in the Era of Letermovir Prophylaxis

Reports suggest that post-transplant cyclophosphamide (PTCy) for haploidentical and HLA-matched sibling donor allogeneic stem cell transplant (allo-SCT) is associated with a higher incidence of cytomegalovirus (CMV) infection than calcineurin inhibitor (CNI) for HLA-matched sibling donor allo-SCT. Prophylactic letermovir has been shown effective for CMV seropositive patients, based on the data mostly before the FDA approval of letermovir (2017). We reevaluated the risk of CMV infection in PTCy transplants. We retrospectively analyzed 175 patients after allo-SCT between May 2019-May 2022). CMV infection was monitored at least for the first year by serostatus, viral load over 500 IU/mL, and/or evidence of CMV end-organ disease. Univariate and multivariate Cox regression analyses were used for the factors, including CMV serostatus, use of letermovir, GVHD prophylaxis, and HLA disparities, to affect the risk of CMV infection and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS). Cumulative incidence curves were used to visualize the incidence of CMV infection stratified by HLA match and PTCY use. A landmark analysis at Day +100 was used for GRFS, where patients who had CMV infection beyond Day +100 (N=13) were assigned to the no-infection group. Of the 175 patients, 108 received HLA-matched donors with GVHD prophylaxis, either CNI (N=70) or PTCy (N=38), while 67 received HLA mismatched donors with either CNI (n=6) or PTCy (N=66) ( Table). Letermovir was given to 137 patients (CMV IgG positive N=130, negative N=7) but not to 38 patients (CMV IgG positive N=12, negative N=26). CMV infection occurred in 28 patients (CMV IgG positive N= 28, CMV IgG negative N=0) before or after Day +100 (N=15 or N=13, respectively). CMV IgG positive recipients not receiving letermovir demonstrated a higher risk of infection by Day +100 than those receiving letermovir (Hazard ratio (HR) 10.1 (95% confidence interval (CI) 3.6-28.6), p&amp;lt;0.01). All 13 infections after Day +100 occurred after the cessation of letermovir (median: 82.9 days after cessation). On univariate analysis, PTCy and HLA mismatch donors increased the risk of CMV infection. The risk of infection by Day +100 increased with PTCy (p=0.07). The risk of infection after Day +100 increased with HLA mismatch donors (p=0.05). In addition, it was confirmed that HLA mismatch allo-SCT with PTCy increased the risk of CMV infection over matched allo-SCT with CNI ( Figure, HR 4.6 (95% CI 1.6-11.9), p&amp;lt;0.01), while HLA match allo-SCT with PTCy did not (p=0.3) (Figure 1). The trend was similar when analyzed only in the case of CMV infection by Day +100 (p&amp;lt;0.05) and after Day +100 (p=0.1). In the 130 CMV IgG seropositive patients who received letermovir, multivariate analysis showed that HLA mismatch donors with PTCy increased the risk of CMV infection over HLA match allo-SCT with CNI. When analyzed only for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome with letermovir (N=91), HLA mismatch transplant with PTCy increased the risk of CMV infection over HLA match transplant with CNI (p=0.05), but not for HLA match transplant with PTCy. Landmark analysis demonstrated better GRFS in the PTCy group than the CNI group and in patients who received PTCy with CMV infection than those who received CNI without CMV infection (p&amp;lt;0.01). PTCy increased the incidence of CMV infection in HLA mismatch allo-SCT by D+100 but not HLA match allo-SCT in the era of letermovir prophylaxis. Patients with PTCy transplant who overcome CMV infection have improved GRFS, possibly due to the increased graft-versus-leukemia effect. Further analysis is required to confirm the difference in the incidence of CMV infection between HLA match and mismatch transplant with PTCy and to assess the significance of late CMV (after Day +100) infection on GRFS.

Cytomegalovirus antigen-specific T cell immune responses in patients with autoimmune diseases under different cytomegalovirus infection status.

Cytomegalovirus antigen-specific T cell immune responses in patients with autoimmune diseases under different cytomegalovirus infection status.

Dissecting human population variation in single-cell responses to SARS-CoV-2.

Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1-3, the genetic and immunological basis of which has begun to be deciphered4. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells-from 222 healthy donors of diverse ancestries-that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.

The Association of Cytomegalovirus and Allostatic Load by Country of Birth and Length of Time in the United States.

Cytomegalovirus (CMV) is a highly prevalent virus with a worldwide distribution. It typically remains dormant in most individuals until reactivation. Immunocompromised states are known to be potential causes for CMV reactivation. Current research has shown a link in the decline of immigrant health among those living in the US for an extended period, though the impact of CMV on this is not clear. This study investigated the association between country of birth, duration of US residency, allostatic load, and latent cytomegalovirus infection (CMV IgG) in a sample of US adults aged 20-49. The data utilized for our analysis was obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2001 and 2004. Allostatic load, an index measuring the cumulative physiological strain on the body as it strives to regain stability in the presence of chronic stress, provided a valuable approach to assess stress within the context of CMV exposure. Logistic regression modeling was employed to estimate odds ratios and confidence intervals for the analysis. The chi-square test of association and Cramer's V statistic were used to assess the correlation among categorical variables, while Pearson's correlation coefficient was applied to evaluate the relationship between continuous variables. The results revealed that individuals born outside the US and those with less than 20 years of residency in the US exhibited significantly higher proportions of positive CMV IgG compared to individuals born in the US. Specifically, individuals born outside the US had more than triple the odds of CMV IgG when adjusting for the AL index (OR = 3.69, p-value = 0.0063). A similar trend was observed when examining AL risk based on the duration of US residency. Furthermore, age and sex were identified as significant predictors (p-value < 0.05) of AL risk, considering the individual's country of birth. In summary, the findings of this study significantly enhance our comprehension of the intricate interplay between cytomegalovirus (CMV) and allostatic load (AL). The investigation sheds light on how CMV and AL interact within specific demographic contexts, providing valuable insights into the underlying risk factors for CMV infection.

Long-term CMV monitoring and chronic rejection in renal transplant recipients.

Cytomegalovirus (CMV) is well established to be an independent risk factor for graft loss after kidney transplantation (KTx). Monitoring for CMV in the chronic phase is not defined in the current guideline. The effects of CMV infection, including asymptomatic CMV viremia, in the chronic phase are unclear. We performed a single-center retrospective study to investigate incidence of CMV infection in the chronic phase, defined as more than 1 year after KTx. We included 205 patients who received KTx between April 2004 and December 2017. The CMV pp65 antigenemia assays to detect CMV viremia were continuously performed every 1-3 months. The median duration of the follow-up was 80.6 (13.1-172.1) months. Asymptomatic CMV infection and CMV disease were observed in 30.7% and 2.9% in the chronic phase, respectively. We found that 10-20% of patients had CMV infections in each year after KTx which did not change over 10 years. The history of CMV infection in the early phase (within 1 year after KTx) and chronic rejection were significantly associated with CMV viremia in the chronic phase. CMV viremia in the chronic phase was significantly associated with graft loss. This is the first study to examine the incidence of CMV viremia for 10 years post KTx. Preventing latent CMV infection may decrease chronic rejection and graft loss after KTx.

Fibroblasts are a site of murine cytomegalovirus lytic replication and Stat1-dependent latent persistence in vivo

To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or higher genome loads than in the previously known sites of murine cytomegalovirus latency. Whereas murine cytomegalovirus gene transcription in PDGFRα-positive fibroblastic cells is almost completely silenced at 5 months post-infection, these cells give rise to reactivated virus ex vivo, arguing that they support latent murine cytomegalovirus infection. Notably, PDGFRα-positive fibroblastic cells also support productive virus replication during primary murine cytomegalovirus infection. Mechanistically, Stat1-deficiency promotes lytic infection but abolishes latent persistence of murine cytomegalovirus in PDGFRα-positive fibroblastic cells in vivo. In sum, fibroblastic cells have a dual role as a site of lytic murine cytomegalovirus replication and a reservoir of latent murine cytomegalovirus in vivo and STAT1 is required for murine cytomegalovirus latent persistence in vivo.

In silico interrogation of the miRNAome of infected hematopoietic cells to predict processes important for human cytomegalovirus latent infection

Human cytomegalovirus (HCMV) latency in CD34+ progenitor cells is the outcome of a complex and continued interaction of virus and host that is initiated during very early stages of infection and reflects pro- and anti-viral activity. We hypothesized that a key event during early infection could involve changes to host miRNAs, allowing for rapid modulation of the host proteome. Here, we identify 72 significantly upregulated miRNAs and three that were downregulated by 6hpi of infection of CD34+ cells which were then subject to multiple in silico analyses to identify potential genes and pathways important for viral infection. The analyses focused on the upregulated miRNAs and were used to predict potential gene hubs or common mRNA targets of multiple miRNAs. Constitutive deletion of one target, the transcriptional regulator JDP2, resulted in a defect in latent infection of myeloid cells; interestingly, transient knockdown in differentiated dendritic cells resulted in increased viral lytic IE gene expression, arguing for subtle differences in the role of JDP2 during latency establishment and reactivation of HCMV. Finally, in silico predictions identified clusters of genes with related functions (such as calcium signaling, ubiquitination, and chromatin modification), suggesting potential importance in latency and reactivation. Consistent with this hypothesis, we demonstrate that viral IE gene expression is sensitive to calcium channel inhibition in reactivating dendritic cells. In conclusion, we demonstrate HCMV alters the miRNAome rapidly upon infection and that in silico interrogation of these changes reveals new insight into mechanisms controlling viral gene expression during HCMV latency and, intriguingly, reactivation.

Human Cytomegalovirus (CMV) Infection Associated With Decreased Risk of Bronchogenic Carcinoma: Understanding How a Previous CMV Infection Leads to an Enhanced Immune Response Against Malignancy.

​Cytomegalovirus (CMV) causes a long-lasting, asymptomatic infection that reportedly has both advantageous and deleterious effects on tumor progression. The purpose of this study was to evaluate the correlation between CMV infection and the incidence of bronchogenic carcinoma. The study was conducted using a Health Insurance Portability and Accountability Act (HIPAA)compliant national database to identify patients both with and without histories of CMV infectionusing International Classification of Diseases (ICD-10 and ICD-9) codes. Access to the database was granted by Holy CrossHealth, Fort Lauderdale for the purpose of academic research with standard statistical methods used to analyze the data. 14,319 patients were included in both the control and CMV-exposed groups and matched by age range and Charlson Comorbidity Index (CCI) scores. The incidence of bronchogenic carcinomawas 1.69% (243/14,319 patients) in the CMV group and 6.08% (871/14,319 patients)in the control group. The difference was statistically significant bya p-value of less than 2.6x10-16 with anodds ratio of 0.26 (95% CI: 0.24-0.30). The two groups were also matched for treatment. Further evaluation of the CMV-specific treatment effects on outcomes was limited due to the insufficient number of treated patients in the control group. This study found a statistically significant correlation between a prior CMV infection and a reduced incidence of bronchogenic carcinoma. This study demonstrates the need for further investigation into how the tumor microenvironment and host immune system are altered by the presence of a latent CMV infection.

267 Defining the single-cell transcriptomes of splenic adaptive Natural Killer cells in donors with latent human cytomegalovirus infection

OBJECTIVES/GOALS: The primary objective of this study was to define the transcriptomes and transcriptional regulatory network required for the development and function of adaptive Natural Killer (NK) cells in donors with latent human cytomegalovirus (HCMV) infection. METHODS/STUDY POPULATION: Eight healthy adult human spleens were obtained from four HCMV seropositive and four HCMV seronegative donors. Spleens were provided by the Versiti Organ Donor Center of Wisconsin and were processed to a single cell suspension. CD7+ CD3E- CD14- CD19- CD20- NK cells were isolated, using the BD FACSAria sorter. Following cell sorting, single-cell RNA sequencing (scRNA-seq) was performed, and cDNA libraries were constructed and sequenced via NextSeq 550. Cell Ranger was then used to algin the cDNA reads and the Seurat R package was used to analyze the transcriptional data. Cells were filtered and clustered based on the number of uniquely expressed genes. The monocle software was used for single cell trajectory analysis and the SCENIC software was used to decipher gene regulatory networks. RESULTS/ANTICIPATED RESULTS: Eight healthy spleens from four HCMV seropositive and four HCMV seronegative donors were obtained and their NK cells were sorted and captured for scRNA-seq. Donor median age was 59 [IQR 48.5-56.5], 50% (n=4) were female and all donors were not experiencing any acute or chronic symptoms. Using scRNA-seq, we observed elevated numbers of NKG2C+ adaptive NK cells in HCMV seropositive individuals when compared to HCMV seronegative individuals. In addition, we identify a set of transcription markers and regulators that are responsible for the development and function of adaptive NKG2C+ NK cells. Finally, our trajectory analysis of adaptive NKG2C+ NK cells revealed a unique developmental pathway. DISCUSSION/SIGNIFICANCE: Here, we demonstrate that HCMV infection can induce the formation of adaptive NKG2C+ NK cells that display a unique transcriptional and developmental profile. These findings have the potential to influence the future application of adaptive NK cells in cellular immunotherapies.

The influence of physical activity level and cytomegalovirus serostatus on the cytokine levels of young individuals

The practice of physical activity (PA) is a non-pharmacological variable that alters the immune response through changes in cytokines and cellular immunity. Inversely latent cytomegalovirus (CMV) infection prematurely ages the immune system and contributes to the chronic inflammatory condition in several diseases and in aging. This study aimed to compare the association of the PA level and CMV serostatus on whole blood mitogen-stimulated cytokine production of young individuals. The resting blood samples were collected from 100 volunteers of both sexes assigned to one of six groups according to the degree of PA and CMV serostatus: sedentary CMV- (n = 15), moderate physical activity CMV- (moderate PA CMV -, n = 15), high physical activity CMV- (high PA CMV-, n = 15), sedentary CMV+ (n = 20), moderate physical activity CMV + (moderate PA CMV+, n = 20) and high physical activity CMV + (high PA CMV +, n = 20). The collected peripheral blood got diluted in supplemented RPMI-1640 culture medium and incubated for 48 h with a 2% concentration of phytohemagglutinin at 37ºC and CO2 at 5%. The supernatants were collected and used for the IL-6, IL-10, TNF-α, and INF-γ analysis by the ELISA method. The IL-10 concentration was higher in the Moderate PA and High PA groups when compared to the sedentary group, regardless of CMV status. The physically active (moderate and high PA) CMV+ individuals presented lower concentrations of IL-6 and TNF-α compared to CMV+ sedentary individuals, and the sedentary CMV+ subjects had a higher concentration of INF-γ compared to Sedentary CMV- subjects (p < 0.05). In summary, it is possible to infer that PA is key to controlling inflammation related to CMV infection. The stimulation of physical exercise is an important factor in controlling many diseases at the populational level.

The immune factors driving DNA methylation variation in human blood

Epigenetic changes are required for normal development, yet the nature and respective contribution of factors that drive epigenetic variation in humans remain to be fully characterized. Here, we assessed how the blood DNA methylome of 884 adults is affected by DNA sequence variation, age, sex and 139 factors relating to life habits and immunity. Furthermore, we investigated whether these effects are mediated or not by changes in cellular composition, measured by deep immunophenotyping. We show that DNA methylation differs substantially between naïve and memory T cells, supporting the need for adjustment on these cell-types. By doing so, we find that latent cytomegalovirus infection drives DNA methylation variation and provide further support that the increased dispersion of DNA methylation with aging is due to epigenetic drift. Finally, our results indicate that cellular composition and DNA sequence variation are the strongest predictors of DNA methylation, highlighting critical factors for medical epigenomics studies.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

Cytomegalovirus infection associated with lower IQ in adolescent patients with schizophrenia spectrum disorders: A preliminary report

Cytomegalovirus (CMV) infection of immunocompetent hosts is usually inapparent, but typically results in a non-silent chronic latency which is considerably more active than previously considered. In adults with schizophrenia spectrum disorders, CMV latent infection has been associated with cognitive disturbance including lower intelligent quotient (IQ). We hypothesized that the same pattern will be present in adolescent patients with schizophrenia spectrum disorders (early-onset non-affective psychosis). We included 17 adolescents with schizophrenia spectrum disorders (10 patients with schizophrenia, one patient with schizoaffective disorder and six patients with psychosis not otherwise specified), mean age 16.7 years, females 71% and CMV seropositivity 35%. Current IQ was estimated with the Wechsler Abbreviated Scale of Intelligence. CMV immunoglobulin G (IgG) concentrations were measured by solid-phase immunoassays and expressed as dichotomous measures (seropositive/CMV + vs. seronegative/CMV-). CMV + patients (mean IQ 91) had significantly lower full-scale IQ than CMV- patients (mean IQ 110) (20 units difference; p < 0.001). Post-hoc analyses showed that CMV + patients had both lower performance and lower verbal IQ relative to CMV- patients (p = 0.001 and 0.049, respectively). In this preliminary report, we found that CMV IgG seropositivity, reflecting previous CMV infection and current latency, was associated with lower IQ. This may be indicative of an unfavorable impact of CMV infection on general intelligence in early-onset non-affective psychosis.