Search Results (43)

Human cytomegalovirus (CMV) remains a significant infectious complication after kidney transplantation, reflecting gaps in the understanding of the molecular and immunological mechanisms regulating the transition from latency to productive infection. Following primary infection, CMV establishes lifelong latency in hematopoietic and myeloid lineage cells, maintained by viral chromatin repression and robust CMV-specific immune surveillance. CMV reactivation is associated with graft dysfunction, increased risk of rejection, opportunistic infections, and reduced patient survival. In kidney transplantation, CMV reactivation is driven by the interplay between tissue injury, inflammation, and immunosuppression. Ischemia–reperfusion injury and peri-operative stress produce reactive oxygen species, DNA damage, and pro-inflammatory cytokines (e.g., TNF-α, IL-6), which activate transcription factors such as NF-κB and AP-1. These factors regulate the CMV major immediate-early promoter (MIEP), thereby triggering lytic viral gene expression. At the same time, immunosuppressive therapies impair antiviral immune surveillance and, in some cases, induce cytokine release, potentially contributing to the pro-inflammatory environment that favors viral reactivation. In this review, we summarize current molecular and immunologic mechanisms governing CMV latency and reactivation with a focus on how immunosuppressive strategies and injury-associated pathways converge to promote CMV reactivation. We also discuss implications of risk stratification and the development of targeted therapeutic strategies to prevent CMV reactivation in kidney transplant recipients (KTRs). Full article

Pregnancy represents a dynamic immunological state in which the maternal immune system must balance tolerance toward the semi-allogeneic fetus while maintaining antimicrobial defense. Cytomegalovirus (CMV) infection is highly prevalent worldwide and profoundly shapes immune cell differentiation and long-term activation in adults. However, its interaction with pregnancy-associated immune remodeling remains incompletely defined. In this prospective longitudinal study, we comprehensively analyzed immune profiles of healthy pregnant women across all three trimesters and age-matched nonpregnant controls, stratified by CMV IgG serostatus. Multiparametric flow cytometry characterized T and B cell subsets and cytokine production following in vitro stimulation, while circulating cytokines and adhesion molecules were quantified using multiplex immunoassay. Gestational age was the primary determinant of leukocyte dynamics. Nevertheless, CMV-seropositive pregnant women showed enhanced activation and differentiation of CD4⁺ and, more prominently, CD8⁺ T cell subsets, changes not observed in nonpregnant women. Despite pronounced cellular differences, serum cytokine and adhesion molecule levels were largely comparable between CMV-seropositive and CMV-seronegative participants in both pregnant and nonpregnant groups. Functionally, CMV-seropositive women exhibited enrichment of IFN-γ– and IL-21–producing T cells, whereas B cell responses remained predominantly IL-10–dominated. These findings indicate selective alterations in maternal lymphocyte activation and function during pregnancy in CMV-seropositive women, without evidence of systemic inflammation. Full article

Background: Herpes simplex virus (HSV), Epstein–Barr virus (EBV), and cytomegalovirus (CMV) establish lifelong latency in sensory neurons, lymphoid tissue, and myeloid–endothelial cells, respectively. A substantial proportion of adults worldwide are infected with all three viruses and may experience concurrent herpesvirus latency, yet they have largely been studied independently. This review examined whether latent and intermittently reactivating herpesviruses share overlapping inflammatory signatures and whether their combined presence contributes to chronic inflammatory burden. Methods: A narrative integrative review was conducted using MEDLINE, Embase, and Google Scholar (inception–October 2025). Evidence from thirty-one cohort studies and mechanistic investigations spanning virology, immunology, neurology, and clinical medicine was synthesized. Results: Herpesvirus reactivation rates ranged from 23% in general Intensive Care Unit (ICU) populations to 85% in severe COVID-19. Concurrent reactivation of multiple viruses occurred in 34–63% of critically ill patients and was associated with worse clinical outcomes. Notably, simultaneous CMV and EBV reactivation independently predicted mortality (adjusted hazard ratio, 3.17; 95% CI, 1.41–7.13). Across infections, overlapping inflammatory biomarkers, including IL-6, TNF-α, CRP, and PGE₂, were consistently elevated, reflecting convergent activation of IFN and NF-κB signaling pathways. Mechanistic studies suggest cross-compartment immune priming, where CMV-driven T-cell exhaustion facilitates EBV reactivation, and viral cytokine signaling enhances HSV-associated neuroinflammation. Conclusions: HSV, EBV, and CMV triple latency may represent an underrecognized contributor to chronic inflammation in immunocompetent hosts. Understanding this multi-virus inflammatory network may inform mechanistic research, biomarker-guided risk stratification, and therapeutic strategies targeting convergent inflammatory pathways. Prospective interventional studies incorporating concurrent multi-virus monitoring are needed to clarify causal relationships. Full article

Background/Objective: Periodontitis and osteoporosis frequently co-occur after menopause, yet the immune–bone pathways linking oral and skeletal phenotypes remain incompletely defined. This study investigated whether periodontitis severity and low bone mineral density (BMD) in postmenopausal women are associated with convergent systemic inflammaging and immunosenescence phenotypes and with a salivary RANKL/OPG imbalance. Methods: In this cross-sectional study, 280 postmenopausal women were assigned to a 2 × 2 factorial design based on periodontal status (severe vs. no/mild) and BMD status (low vs. normal; DXA T-score). Full-mouth periodontal measurements (PD, CAL, BOP, plaque index, tooth count; stage/grade) were recorded. Salivary RANKL and OPG were quantified, and the RANKL/OPG ratio was calculated. Systemic inflammaging markers (hs-CRP, IL-6, TNF-α) and CMV IgG were assessed, and T-cell immune-aging phenotypes were profiled by flow cytometry (CD3, CD4, CD8, CD45RA, CCR7, CD28, CD57, KLRG1, PD-1, CD27). Results: Severe periodontitis and low BMD were each associated with higher salivary RANKL/OPG ratios and greater systemic inflammatory burden, with modest interaction effects. Immune-aging profiles showed higher proportions of late-differentiated CD8+ phenotypes, and CMV seropositivity was strongly associated with immunosenescence markers. Conclusions: In postmenopausal women, periodontal destruction and low BMD were aligned with osteoclastogenic and immune-aging signatures, consistent with oral–skeletal immune crosstalk. Findings should be interpreted as associative rather than causal, and longitudinal observational studies are warranted to clarify temporality. Full article

Cytomegalovirus (CMV) seropositivity associates with cardiovascular disease in healthy adults, but associations are unclear in people living with HIV (PLWH) despite their high CMV burden. However, CMV antibody levels correlated with inflammatory biomarkers only in PLWH who subsequently developed coronary artery disease (CAD), so the effects of CMV in an individual may vary. Here we investigate the role of CMV-encoded interleukin-10 (cmvIL-10) in PLWH on anti-retroviral therapy. Plasma levels of cmvIL-10 and antibodies reactive with a cmvIL-10 peptide or a lysate of CMV-infected fibroblasts were assessed in PLWH with or without CAD. cmvIL-10 was assessed at diagnosis/selection (T0) and 12 months earlier (T-12), with anti-cmvIL-10 also assessed at −24 and −36 months (n = 36–58/group). Plasma cmvIL-10 was recorded as positive in 5–10 PLWH per group, irrespective of CAD status. Of 21 PLWH with detectable cmvIL-10, only six were positive at both timepoints. Anti-cmvIL-10 was measurable in all samples, at levels independent of cmvIL-10, CAD or time of sampling. Amongst PLWH without CAD, the detection of cmvIL-10 associated with higher levels of CXCL10 (T0 and T-12) and lower levels of the IL-1 receptor antagonist (IL-1Ra; T0 only). At T-12, anti-cmvIL-10 correlated with IL-1Ra in PLWH without CAD (p = 0.01), and sCD14 in PLWH with CAD (p = 0.01). Anti-cmvIL-10 correlated with VCAM-1 at several timepoints in both groups. Hence, cmvIL-10 may be produced episodically, inducing anti-cmvIL-10 peptide antibody, which may represent levels of the cytokine averaged over time. Plasma levels of cmvIL-10 and anti-cmvIL-10 antibody associated differently with inflammatory biomarkers in PLWH with and without CAD, suggesting mechanisms by which host responses to CMV may have different clinical consequences. Full article

This study aims to characterise the B cell compartment in a cohort of Sicilian centenarians by analysing absolute CD3⁻CD19⁺ lymphocyte counts, in association with age, sex, cytomegalovirus (CMV) serostatus, related to immune ageing, and interleukin (IL)-6 levels, representative of inflamm-ageing. It also investigates age-related changes in the CD4⁺/CD19⁺ ratio as a marker of immune ageing, reflecting shifts in immune homeostasis. B cell counts were assessed by flow cytometry on 53 Sicilians aged 19–110 years: 20 Adults, 15 Older adults, 11 long-living individuals, and 7 oldest centenarians. A multiple negative binomial regression was applied to evaluate the effects of age, sex, CMV serostatus, and Il-6 levels on values of B cells. The results showed a non-significant trend toward age-related decline without sex-based differences. A significant reduction in B cell count was observed in individuals with high anti_CMV titres, while IL-6 levels showed a borderline inverse correlation. CD4⁺/CD19⁺ ratio values showed an age-related increase. Our findings suggest that the age-related decline in B cell numbers may be mostly related to CMV infection and IL-6 values, without sex contribution. The age-related increase in the CD4⁺/CD19⁺ ratio, most pronounced in oldest centenarians, may represent a compensatory adaptation promoting immune regulation and chronic inflammation control. Full article

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT. Full article

Cytomegalovirus (CMV) is the leading infectious cause of birth defects and has been linked to increased risk of preterm birth (PTB). CMV establishes lifelong latency and is more prevalent among Black and Hispanic/Latina women, populations already at higher risk for adverse pregnancy outcomes. Vitamin D deficiency, also common in these groups, has been linked to impaired immune function and increased susceptibility to infections, including CMV. In this cross–sectional study of 63 pregnant minority women (50 CMV+, 13 CMV−), we evaluated associations among serum 25(OH)D levels, CMV serostatus, and cmvIL–10, the CMV–encoded interleukin–10 homolog that modulates host immune responses. While vitamin D insufficiency and CMV seropositivity were both highly prevalent, we found no statistically significant associations between 25(OH)D levels and CMV serostatus or cmvIL–10 levels. These findings highlight the need for further investigation into how vitamin D deficiency and CMV infection may independently or synergistically contribute to maternal and neonatal health disparities. Full article

Cytomegalovirus (CMV) is implicated in cardiovascular disease in healthy adults and after transplantation, but analyses in people living with HIV (PLWH) are difficult as almost all have CMV co-infections. Here, we address whether coronary artery disease (CAD) is associated with levels of CMV-reactive antibodies or with sensitivity to inflammation associated with CMV. PLWH stable on antiretroviral therapy (ART) with a recent diagnosis of CAD were matched with PLWH without CAD. Plasma samples stored at the time of the CAD event and 6, 12, 24 or 36 months earlier (n = 34–55 per group) were used for analyses. Antibodies reactive with a lysate from CMV infected cells were quantitated using an in-house ELISA, and inflammatory biomarkers were assessed using commercial kits. Bivariate analyses demonstrated similar levels of CMV antibodies in PLWH with and without CAD at all time points (p > 0.5). However, in PLWH with CAD, levels of CMV antibody correlated directly with plasma sCD14, LBP, CXCL10 and/or IL-6 at the earlier points. These correlations were not impacted by detectable plasma HIV RNA. Our findings suggest that individual differences in sensitivity to the inflammatory effects of CMV impact upon the development of CAD. Full article

Background and Clinical Significance: Hemophagocytic lymphohistiocytosis (HLH) and autoimmune hemolytic anemia (AIHA) are both life-threatening hematologic syndromes that rarely present together outside of malignancy. Advanced acquired immunodeficiency syndrome (AIDS) creates a milieu of profound immune dysregulation and hyperinflammation, predisposing patients to atypical overlaps of these disorders. Case Presentation: A 30-year-old woman with poorly controlled AIDS presented with three weeks of jaundice, fever, and fatigue. Initial labs revealed pancytopenia, hyperbilirubinemia, and elevated ferritin level. Direct anti-globulin testing confirmed warm AIHA (IgG⁺/C3d⁺) with transient cold agglutinins. Despite intravenous immunoglobulin (IVIG), rituximab, and transfusions, she developed hepatosplenomegaly, extreme hyperferritinemia, and sIL-2R > 10,000 pg/mL, meeting HLH-2004 criteria. Bone marrow biopsy excluded malignancy; further work-up revealed Epstein–Barr virus (EBV) viremia and cytomegalovirus (CMV) reactivation. Dexamethasone plus reduced-dose etoposide transiently reduced soluble interleukin-2 receptor (sIL-2R) but precipitated profound pancytopenia, Acute respiratory distress syndrome (ARDS) from CMV/parainfluenza pneumonia, bilateral deep vein thrombosis (DVT), and an ST-elevation myocardial infarction (STEMI). She ultimately died of hemorrhagic shock after anticoagulation despite maximal supportive measures. Conclusions: This case underscores the diagnostic challenges of HLH-AIHA overlap in AIDS, where cytopenias and hyperferritinemia mask the underlying cytokine storm. Pathogenesis likely involved IL-6/IFN-γ overproduction, impaired cytotoxic T-cell function, and molecular mimicry. While etoposide remains a cornerstone of HLH therapy, its myelotoxicity proved catastrophic in this immunocompromised host, highlighting the urgent need for cytokine-targeted agents to mitigate treatment-related mortality. Full article

Background: Chronic cytomegalovirus (CMV) infection may favor the development of immunosenescence and inflammation that impair vaccine responses, including COVID-19. In addition, the polymorphism of the interferon-lambda gene (IFNλ) affects COVID-19 immune responses in older adults. Objective: We aimed to investigate the impact of IFNλ polymorphism (IL28B gene-rs12979860) on the immune/inflammatory response to vaccination with CoronaVac for COVID-19 in older adults who were CMV-seropositive. Methods: Blood samples from 42 CMV-seropositive older adults (73.7 ± 4.5 years) were collected before and 30 days after immunization with a second dose of the CoronaVac vaccine to evaluate the immune/inflammatory response. Results: At genotyping, 20 subjects were homozygous for the C/C alleles (Allele-1 group), 5 were homozygous for the T/T Alleles (Allele-2 group), and 17 were heterozygous (C/T, Alleles-1/2 group). The Allele-1 group showed higher IgG levels for COVID-19 (p = 0.0269) and intermediate monocyte percentage (p = 0.017), in contrast to a lower non-classical monocyte percentage (p = 0.0141) post-vaccination than pre-vaccination. Also, this group showed that IgG levels for CMV were positively associated with a systemic pro-inflammatory state and senescent T cells (CD4+ and CD8+). The Allele-2 group presented higher IFN-β levels at pre- (p = 0.0248) and post-vaccination (p = 0.0206) than the values in the Allele-1 and Alleles-1/2 groups, respectively. In addition, the Allele-2 and Alleles-1/2 groups showed that IgG levels for COVID-19 were positively associated with a balanced systemic inflammatory state. Conclusion: CMV-seropositivity in older adults who had Allele-1 could lead to an unbalanced systemic inflammatory state, which may impair their antibody response to COVID-19 vaccination compared to other volunteer groups. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency in the host, with the bone marrow (BM) CD34+ cells serving as a key reservoir. To investigate tissue-specific immune responses to CMV, we analysed paired peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMNCs) from HCMV-seropositive donors using multiparametric flow cytometry and cytokine FluroSpot assays. We assessed immune cell composition, memory T cell subsets, cytokine production, cytotoxic potential, activation marker expression, and checkpoint inhibitory receptor (CIR) profiles, both ex vivo and following stimulation with lytic and latent HCMV antigens. BMMNCs were enriched in CD34+ progenitor cells and exhibited distinct T cell memory subset distributions. HCMV-specific responses were compartmentalised: IFN-γ responses predominated in PBMCs following lytic antigen stimulation, while IL-10 and TNF-α responses were more prominent in BMMNCs, particularly in response to latent antigens. US28-specific T cells in the BM showed elevated expression of CD39, PD-1, BTLA, CTLA-4, ICOS, and LAG-3 on CD4+ T cells and increased expression of PD-1, CD39, BTLA, TIGIT, LAG-3, and ICOS on CD8+ T cell populations, suggesting a more immunoregulatory phenotype. These findings highlight functional and phenotypic differences in HCMV-specific T cell responses between blood and bone marrow, underscoring the role of the BM niche in shaping antiviral immunity and maintaining viral latency. Full article

Human cytomegalovirus (HCMV) is a high-risk pathogen in immunocompromised individuals, especially in transplant recipients. HCMV viremia must be monitored, and frequently, patients are treated with antiviral agents. HCMV has a variety of strategies to modulate host antiviral responses, and one important player is a viral homolog of the cellular interleukin-10 (cIL-10). The viral UL111A gene produces several HCMV IL-10 transcripts and protein isoforms through alternative splicing. The cmvIL-10 (isoform A) has similar properties to cIL-10, while LAcmvIL-10 (isoform B) has more restricted biological properties. Other isoforms are produced (C to H) but have unknown functions. Here, we investigated the expression of the most abundant transcripts, cmvIL-10 and LAcmvIL-10, in productively and latently infected cells and in peripheral blood mononuclear cells from renal transplant recipients up to 60 days post-transplantation. This study investigated HCMV cmvIL-10 and LAcmvIL-10 transcription profiles in vitro, in productive and latent infection, and in vivo, in peripheral blood mononuclear cells (PBMCs) of renal transplant patients. In vitro, both cmvIL-10 and LAcmvIL-10 transcripts were detected in both types at high levels and low levels in MRC-5 and latent infected (CD14+). When PBMCs from transplant patients were analyzed, LAcmvIL-10 was detected mostly sporadically and in only a few patients, while cmvIL-10 was found in all patients at all time points. Furthermore, it was observed in PBMCs that expression of cmvIL-10 was positively associated with an increase in viral DNA detection in the subsequently collected sample, indicating that expression of cmvIL-10 might precede viral DNA replication. These results contribute to the understanding of HCMV biology in different phases of infection. In addition, our initial analysis suggests that monitoring cmvIL-10, along with viral DNA, could improve early detection of HCMV reactivation in transplant recipients. Full article

Previously, we reported on the peptide–HLA-I fusion protein EpCAM-ReTARG^TPR, which allows us to redirect the cytotoxic activity of pre-existing anti-CMV CD8^pos T cell immunity to selectively eliminate EpCAM^pos cancer cells. EpCAM-ReTARG^TPR consists of the CMV pp65-derived peptide TPRVTGGGAM (TPR) fused in tandem with a soluble HLA-B*07:02/β2-microglobulin (β2M) molecule and an EpCAM-directed Fab antibody fragment. To further enhance its anticancer activity, we equipped EpCAM-ReTARG^TPR with the immune-potentiating cytokine muteins IL2^(H16A,F42A) and IFNα^R149A, respectively. Both cytokines are engineered to have attenuated affinity for their respective cytokine receptors. Compared to EpCAM-ReTARG^TPR, in vitro treatment of EpCAM^pos carcinoma cell lines with EpCAM-ReTARG^TPRvIL2 for 24 h increased the cytotoxic activity of PBMCs containing low levels of TPR-specific CD8^pos T cells by ~15%, whereas EpCAM-ReTARG^TPRIFNα^R149A induced an increase of ~50%. Moreover, treatment for 120 h with EpCAM-ReTARG^TPRIFNα^R149A inhibited the proliferative capacity of the cancer cell lines OvCAR3 and PC3M by ~91% without compromising the viability of the TPR-specific CD8^pos T cells and increased their capacity for IFNγ secretion. Importantly, EpCAM-ReTARG^TPRIFNα^R149A potently induced the elimination of primary EpCAM^pos refractory carcinoma cells from a Merkel cell carcinoma (MCC) patient. Taken together, the armoring of the carcinoma-directed peptide–HLA-I fusion protein EpCAM-ReTARG^TPR with IFNα^R149A potently enhanced the efficacy of pre-existing anti-CMV CD8^pos T cell immunity to selectively eliminate EpCAM^pos cancer cells. Full article

Background: Cytokine Release Syndrome (CRS) is a hyperinflammatory state triggered by immune therapies like CAR T-cell therapy and bispecific T-cell engagers (BiTEs). Characterized by excessive cytokine release, CRS often mimics infectious and inflammatory conditions, complicating diagnosis and treatment. Immunosuppressive therapies used for CRS further elevate the risk of secondary infections. Methods: A systematic search of PubMed and EMBASE was conducted using terms related to “cytokine release syndrome”, “cytokine storm”, “infections”, and “management”. Studies were included if they described infectious complications, diagnostic mimics, or therapeutic approaches related to CRS. Results: Of 19,634 studies, 2572 abstracts were reviewed. Infections occurred in up to 23% of patients post-CAR T therapy and 24% post-BiTE therapy. Pathogens included gram-positive and gram-negative bacteria, herpesviruses (e.g., CMV, HSV), fungi (e.g., Candida, Aspergillus), and parasites (e.g., Toxoplasma gondii). CRS mimics also included non-infectious inflammatory syndromes. Differentiation remains challenging, but cytokine profiling and biomarkers (e.g., ferritin, CRP, sIL-2Rα) may aid in diagnosis. Treatments included tocilizumab, corticosteroids, and empiric antimicrobials. Prophylactic strategies were inconsistently reported. Conclusions: Effective CRS management requires early recognition, differentiation from infectious mimics, and collaboration between oncology and infectious disease (ID) specialists. A multidisciplinary, collaborative, and structured approach, including dedicated ID input and pre-treatment evaluation, is essential for optimizing CRS management and patient outcomes. Full article