Chronic Viral Infections Research Articles

Efficacy of differentiated targeted interferon and immunomodulatory therapy focused on pathological immunophenotypes in patients with atypical chronic active herpesvirus infections

Objective: In a prospective cohort study to evaluate the clinical and immunological efficacy of differentiated targeted interferon and immunomodulatory therapies focused on identified pathological immunophenotropes and associated clinical manifestations in immunocompromised patients suffering from atypical chronic active herpes viral infections (ACA-HVI).Materials and methods: 335 patients suffering from mixed-AHA-HVI were examined. The study complex included: methods for detecting herpesviruses: serodiagnosis, PCR-RV; immunological methods: a research of subpopulation of blood lymphocytes (method of a flow cytometry), determination of the spontaneous and induced products of IFNα and IFNγ, levels of serum cytokines and immunoglobulins (IL-1β, IL-6, IL-17, TNFα and IFNα and IFNγ, Ig A, M, G) by ELISA. The study was approved by the ethics board and informed consent was obtained from all patients.Results: Integral formulas of disorders in the antiviral immune defense system were created, which made it possible to isolate 3 pathological immunophenotypes (PIF): PIF1: NG↓+ind.IFNα/IFNγ↓+CTL↓+EKK↓+IgM↑+hypecytokinemiya (IL-1β↑+IL-6↑+TNFα↑); PIF2: NG↓+ ind. IFNα/IFNγ↓ + EKK↓+ IgG↓+hypercytokinemiya (IL-1β↑+IL-6↑+TNFα↑) and PIF3: NG↓+ind.IFNα/IFNγ↓+hypercytokinemiya (IL-1β↑+IL- 6↑+TNFα↑). Taking into account the identified disorders, a program of targeted interferon and immunomodulatory therapy was developed for each PIF: local and systemic IFN therapy + hexapeptide was developed for PIF1; for PIF2- local and systemic IFN therapy + glucosaminimuramyldipeptide; for PIF3-local and systemic IFN therapy.Conclusions: High clinical efficacy was demonstrated in 100% of patients with three groups of ACA-HVI. Immunological effectiveness of targeted interferon and immunomodulatory therapy programs: 89.5% for PIF1; for PIF2-57.6% and for PIF3- 37.5% of cases.

Production of the Proinflammatory Cytokine TNF-α in Patients with Chronic Epstein-Barr Virus Infection

Aim of the Study: Study of the production of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in patients with Chronic Epstein-Barr Viral Infection (CEBI). Material and Methods: 90 patients with CVEBI were examined. The group consisted of 66 women and 24 men. The average age of the patients was 38.37 ± 1.15 years. The duration of the course of CVEBI from the appearance of the patient’s first complaints to diagnosis was 3.73 ± 0.22 years. The amount of EBV DNA in saliva samples (PCR method) and the level of production of the cytokine TNF-α ware examined in patients. Results: The copy number of EBV DNA in saliva samples from patients was 135898.61±23196.21 cop/ml. The level of induced TNF-α in the general group was 3288.73±260.88. All patients were divided into three groups: group 1 (n = 49) - the level of induced TNF-α was reduced - 1624.69±105.53 (pg/ ml) (95% CI: 1412.52; 1836.86) ; Group 2 (n =30) - the level of induced TNF-α is normal - 3819.19 ±427.00 (pg/ml) (95% CI: 3045.27; 4701.81); Group 3 (n =11) the level of induced TNF-α is high – 7203.00 ± 627.50 (pg/ml) (95% CI: 6135.37 - 8609.87). Patients did not differ in age, disease duration, or number of EBV DNA copies in saliva samples. The linear and exponential regression method was used to show the effect of disease duration on the level of TNF-α production in the general group of patients (R2 =0.386 F=55.925 p=0.0001 β=0.621 and R2 =0.735 F=246.808 p=0.0001 β=0.857, respectively). TNF-α influences the development of headaches in patients (Pearson correlation R = 0.223 p = 0.040) and the severity of postnasal drip (r = -0.231 p = 0.033 τ = - 0.171 p = 0.039). Conclusion: The study showed that the duration of the disease affects the level of production of induced TNF-α. TNF-α levels contribute to the development of headaches and postnasal drip in patients in the general group.

Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate model (NHP) of HIV infection, we evaluated two CAR-based gene therapy approaches. In ACT approach, we utilized cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR+ T cells. We observed limited persistence and expansion of anti-HIV CAR T cells which led to minimal control of the virus. In our stem-cell based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest a stem cell-based CAR T cell approach may be superior to generate long-term persistence and functional antiviral responses against HIV infection.

IFNα Subtypes in HIV Infection and Immunity.

Type I interferons (IFN), immediately triggered following most viral infections, play a pivotal role in direct antiviral immunity and act as a bridge between innate and adaptive immune responses. However, numerous viruses have evolved evasion strategies against IFN responses, prompting the exploration of therapeutic alternatives for viral infections. Within the type I IFN family, 12 IFNα subtypes exist, all binding to the same receptor but displaying significant variations in their biological activities. Currently, clinical treatments for chronic virus infections predominantly rely on a single IFNα subtype (IFNα2a/b). However, the efficacy of this therapeutic treatment is relatively limited, particularly in the context of Human Immunodeficiency Virus (HIV) infection. Recent investigations have delved into alternative IFNα subtypes, identifying certain subtypes as highly potent, and their antiviral and immunomodulatory properties have been extensively characterized. This review consolidates recent findings on the roles of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus (SIV) infections. It encompasses their induction in the context of HIV/SIV infection, their antiretroviral activity, and the diverse regulation of the immune response against HIV by distinct IFNα subtypes. These insights may pave the way for innovative strategies in HIV cure or functional cure studies.

HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING.

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

Outcome of Infants Born to Women with Chronic Hepatitis B: A Local Risk-Based Strategy in a Low Prevalence Country.

Chronic hepatitis-B virus (HBV) infection due to mother-to-child transmission (MTCT) during the perinatal period is an important global health concern. Chile is a low-prevalence country with an increasing migratory inflow from Latin- American countries, with intermediate to high endemic rates of HBV infection, and until 2021, there is no universal maternal screening. This study aimed to evaluate infant outcomes using a risk-based strategy of maternal screening to prevent MTCT of hepatitis B virus (HBV) in a low-prevalence country. This prospective study included infants born to HBsAg-positive women detected using a local risk-based strategy. The exposed infants received immunoprophylaxis (IP) and follow-up to evaluate their clinical outcomes and immune responses through post-serological vaccine testing (PSVT) after completing the three- dose schedule of the HBV vaccine. A total of 99 HBsAg-positive mothers were detected. Seventy-six (82%) infants completed the follow-up and had PSVT between 9 and 12 months of age. 55.2% female, the median gestational age was 39 weeks (25-41) and the median birth weight was 3,130g (816-4,400 g). All patients received IP with recombinant HBV vaccine plus hepatitis-B virus immunoglobulin (HBIG) and three doses of the HBV vaccine. There were no cases of HBV infection, and 96% (72) responded to immunization with HBsAg antibodies (anti-HBsAg) >10 UI/ml, with a median level of 799 IU/ml. A high-risk strategy can be implemented in countries with non-universal screening for VHB. Timely IP plus high-uptake VHB vaccination in infants born to HBsAg-positive mothers was associated with a high immunogenic response and absence of MTCT.

Hypothesis of a CD137/Eomes activating axis for effector T cells in HPV oropharyngeal cancers

Chronic Human Papilloma Virus (HPV) infection is supplanting alcohol and tobacco intoxications as the leading cause of oropharyngeal cancer in developed countries. HPV-related squamous cell carcinomas of the oropharynx (HPV + OSC) present better survival and respond better to radiotherapy and chemotherapy. Regulatory T cells (TREG) are mainly described as immunosuppressive and protumoral in most solid cancers. However, TREG are paradoxically associated with a better prognosis in HPV + OSCs. The transcription factor FoxP3 is the basis for the identification of TREG. Among CD4 + FoxP3 + T cells, some have effector functions. A medical hypothesis is formulated here: the existence of a CD137 (4.1BB)-Eomesodermin (Eomes) activated pathway downstream of TCR-specific activation in a subpopulation of CD4 + FoxP3 + T cells may explain this effector function. Evidence suggest that this axis may exist either in CD4 + FoxP3 + T cells or CD8 + T cells. This pathway could lead T cells to strong antitumor cytotoxic activity in a tumor-specific manner. Furthermore, CD137 is one of the most expected targets for the development of agonist immunotherapies. The identification of CD137 + Eomes + FoxP3+/- T cells could be a key element in the selective activation of the most anti-tumor cells in the HPV + OSC microenvironment.

Imprinted immune abnormalities in liver transplant patients cured of hepatitis C with antiviral drugs.

Chronic HCV infection induces interferon and dysregulates immune responses through inflammation and chronic antigenic stimulation. Antiviral drugs can cure HCV, providing a unique opportunity to examine the immunological restoration that does and does not occur when a chronic viral infection is eradicated. We quantified blood cytokines levels and used mass cytometry to immunophenotype peripheral blood mononuclear cells before and after HCV cure in 2 groups of patients and controls. At baseline, serum interferon α and soluble CD163 (a macrophage product) were elevated in both liver transplant and nonliver transplant patients compared to controls; the frequencies of several peripheral blood mononuclear cell populations differed from controls; and programmed death protein 1-positivity was increased in nearly all T cell subsets. Many abnormalities persisted after HCV cure, including elevated programmed death protein 1 expression on CD4 naïve and central memory T cells, elevated soluble CD163, and expansion of the plasmablast/plasma cell compartment. Several myeloid-lineage subsets, including Ag-presenting dendritic cells, remained dysregulated. In mechanistic studies, interferon α treatment increased programmed death protein 1 on human T cells and increased T cell receptor signaling. The data identify immunological abnormalities that persist after curative HCV treatment. Before cure, high levels of interferon α may stimulate programmed death protein 1 expression on human T cells, causing persistent functional changes.

Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection.

Chronic Human Immunodeficiency Virus (HIV) infection remains a significant challenge to global public health. Despite advances in antiretroviral therapy (ART), which has transformed HIV infection from a fatal disease into a manageable chronic condition, a definitive cure remains elusive. One of the key features of HIV infection is chronic immune activation and inflammation, which are strongly associated with, and predictive of, HIV disease progression, even in patients successfully treated with suppressive ART. Chronic inflammation is characterized by persistent inflammation, immune cell metabolic dysregulation, and cellular exhaustion and dysfunction. This review aims to summarize current knowledge of the interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection, and also discusses the use of humanized mice models to study HIV immune pathogenesis and develop novel therapeutic strategies.

Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.

The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties.

Probiotics, known to be live microorganisms, have been shown to improve or restore the gut microbiota, which in turn has been linked to improved health. It is believed that probiotics are the modern equivalent of a panacea, with claims that they may treat or prevent different diseases both in children and adults (e.g., from colic in babies to cardiovascular disease, respiratory infection, and cancer in adults). Ever since the early 2000s, probiotic-based fermented foods have had a resurgence in popularity, mostly due to claims made regarding their health benefits. Fermented foods have been associated with the prevention of irritable bowel syndrome, lactose intolerance, gastroenteritis, and obesity, but also other conditions such as chronic diarrhea, allergies, dermatitis, and bacterial and viral infections, all of which are closely related to an unhealthy lifestyle. Recent and ongoing developments in microbiome/microbiota science have given us new research directions for probiotics. The new types, mechanisms, and applications studied so far, and those currently under study, have a great potential to change scientific understanding of probiotics' nutritional applications and human health care. The expansion of fields related to the study of the microbiome and the involvement of probiotics in its improvement foreshadow an era of significant changes. An expanding range of candidate probiotic species is emerging that can address newly elucidated data-driven microbial niches and host targets. In the probiotic field, new variants of microbiome-modulating interventions are being developed, including prebiotics, symbiotics, postbiotics, microbial consortia, live biotherapeutic products, and genetically modified organisms, with renewed interest in polyphenols, fibers, and fermented foods to ensure human health. This manuscript aims to analyze recent, emerging, and anticipated trends in probiotics (sources, doses, mechanism of action, diseases for which probiotics are administered, side effects, and risks) and create a vision for the development of related areas of influence in the field.

Late transplant-associated thrombotic microangiopathy verified in bone marrow biopsy specimens is associated with chronic GVHD and viral infections.

To describe late transplant-associated thrombotic microangiopathy (TA-TMA) as chronic endothelial complication in bone marrow (BM) after allogeneic hematopoietic stem cell transplantation (HSCT). BM specimens along with conventional diagnostic parameters were assessed in 14 single-institutional patients with late TA-TMA (more than 100 days after HCST), including 11 late with history of early TA-TMA, 10 with early TA-TMA (within 100 days), and 12 non TA-TMA patients. Three non-HSCT patients served as control. The time points of BM biopsy were +1086, +798, +396, and +363 days after HSCT, respectively. Late TA-TMA patients showed an increase of CD34+ and von Willebrand Factor (VWF)+ microvascular endothelial cells with atypical VWF+ conglomerates forming thickened VWF+ plaque sinus in the BM compared to patients without late TA-TMA and non-HSCT. Severe chronic (p = .002), steroid-refractory GVHD (p = .007) and reactivation of HHV6 (p = .002), EBV (p = .003), and adenovirus (p = .005) were pronounced in late TA-TMA. Overall and relapse-free survival were shorter in late TA-TMA than in patients without late TA-TMA (5-year OS and RFS: 78.6% vs. 90.2%, 71.4% vs. 86.4%, respectively). Chronic allo-immune microangiopathy in BM associated with chronic, steroid-refractory GVHD and/or viral infections are key findings of late, high-risk TA-TMA, which deserves clinical attention.

Neonatal CD8+ T Cells Resist Exhaustion during Chronic Infection.

Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.

Abstract A051: PSGL-1-deficiency promotes pancreatic ductal adenocarcinoma tumor control and synergy with immune checkpoint blockade

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, poorly immunogenic cancer with increasing incidence rates while patient prognosis remains poor with a 5-year survival rate of only 12%. PDAC tumors are refractory to all currently available treatments, including existing immune checkpoint blockade (ICB) therapies, and demonstrate limited T cell infiltration. There is a critical need to develop novel approaches to improve patient outcomes. We previously demonstrated that deficiency of P-selectin glycoprotein 1 (PSGL-1) promotes enhanced T cell responses that clear chronic LCMV Cl13 virus infection and inhibit growth of PD-1 blockade resistant melanoma. Here we evaluated if targeting PSGL-1 promotes T cell responses to PDAC tumors to inhibit growth and metastases. KPC.4662 tumor cells were injected orthotopically into the tail of the pancreas of C57BL/6 (wildtype control) and PSGL-1−/− (C57BL/6 background) male or female mice and tumor growth and immune infiltration was evaluated by histology and flow cytometry. At 28 days post-orthotopic tumor cell injection, KPC.4662 tumor burden was reduced by 50% on average (1.1 g vs 0.45g) in PSGL-1−/− mice compared to controls. Total immune infiltration (CD45+) was increased in tumors from PSGL-1−/- mice (10% vs 24%), with a significant increase in CD3+ T cell infiltration. Moreover, fewer mice developed metastases in the peritoneal cavity, liver, and lungs. To assess if PSGL-1−/− mice had the capability to reduce metastatic burden, KPC 4662 tumor cells were injected intravascularly and tumor development in the lungs was assessed on day 17. PSGL-1−/− mice reproducibly developed fewer tumors in the lungs compared to wildtype control mice as determined by histological examination. To address if enhanced control of PDAC tumors was mediated by T cells, we depleted CD4+ and CD8+ T cells immediately prior to orthotopic implantation of KPC.4662 tumor cells. Depletion of T cells resulted in the loss of PDAC tumor growth control in PSGL-1−/− mice. Given our previous studies demonstrating an intrinsic role for PSGL-1 in the development of T cell exhaustion, we hypothesized that PSGL-1-deficiency would promote responsiveness to PD-1 immune checkpoint blockade, a therapy known to be ineffective as a monotherapy in PDAC patients and mouse models. When PD-1 blocking antibody was therapeutically administered on days 10, 12, and 14 post-tumor implantation, 85% of PSGL-1−/− animals demonstrated complete responses. From these studies, we conclude that in the absence of PSGL-1, we observe significantly reduced growth of primary orthotopic PDAC tumors and decreased metastases. These findings are associated with increased CD45+ immune cell infiltration in the tumors and notably functions in a T cell-dependent manner. PSGL-1 therefore represents a novel target for promoting immune responses to PDAC tumors. Citation Format: Jennifer L. Hope, Yijuan Zhang, Hannah A. Faso, Sreeja Roy, Michelle Lin, Ashley B. Palete, Swetha Maganti, Dennis C. Otero, Cosimo Commisso, Linda M. Bradley. PSGL-1-deficiency promotes pancreatic ductal adenocarcinoma tumor control and synergy with immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A051.

Safety and Virologic Impact of Haploidentical NK Cells Plus Interleukin 2 or N-803 in HIV Infection.

Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. We conducted a phase 1 pilot study in 6 persons with HIV (PWH), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). The approach was well tolerated with no unexpected adverse events. We did not pretreat recipients with cyclophosphamide or fludarabine to "make immunologic space," reasoning that PWH on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (similar to what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA-positive cells in lymph nodes. There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy. Clinical Trials Registration. NCT03346499 and NCT03899480.

Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.

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.

Ten-eleven translocation (Tet) methylcytosine dioxygenase-dependent viral DNA demethylation mediates in vivo hepatitis B virus (HBV) biosynthesis.

Liver-specific ten-eleven translocation (Tet) methylcytosine dioxygenases 2 and 3 (Tet2 plus Tet3)-deficient hepatitis B virus (HBV) transgenic mice fail to support viral biosynthesis. The levels of viral transcription and replication intermediates are dramatically reduced. Hepatitis B core antigen is only observed in a very limited number of pericentral hepatocytes in a pattern that is similar to glutamate-ammonia ligase (Glul), a β-catenin target gene. HBV transcript abundance in adult Tet-deficient mice resembles that observed in wild-type neonatal mice. Furthermore, the RNA levels of several β-catenin target genes including Glul, Lhpp, Notun, Oat, Slc1a2, and Tbx3 in Tet-deficient mice were also similar to that observed in wild-type neonatal mice. As HBV transcription is regulated by β-catenin, these findings support the suggestion that neonatal Tet deficiency might limit β-catenin target gene expression, limiting viral biosynthesis. Additionally, HBV transgene DNA displays increased 5-methylcytosine (5mC) frequency at CpG sequences consistent with neonatal Tet deficiency being responsible for decreased developmental viral DNA demethylation mediated by 5mC oxidation to 5-hydroxymethylcytosine, a process that might be responsible for the reduction in cellular β-catenin target gene expression and viral transcription and replication.IMPORTANCEChronic hepatitis B virus (HBV) infection causes significant worldwide morbidity and mortality. There are no curative therapies available to resolve chronic HBV infections, and the small viral genome limits molecular targets for drug development. An alternative approach to drug development is to target cellular genes essential for HBV biosynthesis. In the liver, ten-eleven translocation (Tet) genes encode cellular enzymes that are not essential for postnatal mouse development but represent essential activities for viral DNA demethylation and transcription. Consequently, Tet inhibitors may potentially be developed into therapeutic agents capable of inducing and/or maintaining HBV covalently closed circular DNA methylation, resulting in transcriptional silencing and the resolution of chronic viral infection.

Association between chronic viral infection-related hospitalization and risk of cardiovascular disease: Apopulation-based cohort study.

Chronic viral infection induces immunosenescence and systemic low-grade inflammation, leading to worsened long-term outcomes. We sought to explore the short- and long-term effects of chronic viral infection on cardiovascular disease (CVD). Based on UK Biobank data, exposed group was identified as individuals who had chronic virus infection-related hospitalization (IRH). Unexposed group was randomly selected, matched by 5-year age interval, sex, and Charlson comorbidity index at a ratio up to 1:10. Restricted cubic splines were used to model time-varying effects of IRH in nonproportional Cox models. A cut-off value of 5 years was recorded and used in piecewise Cox proportional hazards models as we estimated short- and long-term effects of IRH on CVD. A total of 2826 exposed participants and 28 212 matched unexposed participants were included. Chronic viral IRH was associated with increased risk of CVD (0-5 years: hazard ratio, 1.57 [95% confidence interval: 1.32, 1.87] and 5+ years: 1.31 [1.06, 1.61]). Elevated risk of stroke was only observed within the initial 5-year follow-up (0-5 years: 1.91 [1.30, 2.81]). The short- and long-term associations were observed in herpes or hepatitis virus IRH with risk of CVD (all p < 0.05). Subgroup analysis revealed long-term association between chronic viral IRH and CVD among female (5+ years: 1.68 [1.27, 2.22]) but not among male. The association between chronic viral infection and elevated CVD risk appeared to be stronger among individuals who did not take cholesterol-lowering medication, antithrombotic medication, or certain antihypertensive medications (all p for interaction < 0.05). The risk of CVD event remained persistently higher within and over 5 years following chronic viral IRH, especially in individuals infected with herpes and hepatitis virus.

Single-cell RNA sequencing reveals the dynamics and heterogeneity of lymph node immune cells during acute and chronic viral infections.

The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient. To explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45+ immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections. In contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA+ plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8+ T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4+ T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8+ and CD4+ T cells. In conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.