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Viral infection leads to heterogeneous cellular outcomes ranging from refractory to abortive and fully productive states. Single cell transcriptomics enables a high resolution view of these distinct post-infection states. Here, we have interrogated the host-pathogen dynamics following reactivation of Epstein-Barr virus (EBV). While benign in most people, EBV is responsible for infectious mononucleosis, up to 2% of human cancers, and is a trigger for the development of multiple sclerosis. Following latency establishment in B cells, EBV reactivates and is shed in saliva to enable infection of new hosts. Beyond its importance for transmission, the lytic cycle is also implicated in EBV-associated oncogenesis. Conversely, induction of lytic reactivation in latent EBV-positive tumors presents a novel therapeutic opportunity. Therefore, defining the dynamics and heterogeneity of EBV lytic reactivation is a high priority to better understand pathogenesis and therapeutic potential. In this study, we applied single-cell techniques to analyze diverse fate trajectories during lytic reactivation in three B cell models. Consistent with prior work, we find that cell cycle and MYC expression correlate with cells refractory to lytic reactivation. We further found that lytic induction yields a continuum from abortive to complete reactivation. Abortive lytic cells upregulate NFκB and IRF3 pathway target genes, while cells that proceed through the full lytic cycle exhibit unexpected expression of genes associated with cellular reprogramming. Distinct subpopulations of lytic cells further displayed variable profiles for transcripts known to escape virus-mediated host shutoff. These data reveal previously unknown and promiscuous outcomes of lytic reactivation with broad implications for viral replication and EBV-associated oncogenesis. Author summary: Viral infections profoundly alter host cell biological programming in ways that potentiate disease. Epstein-Barr virus (EBV) is a particularly prevalent human pathogen associated with diverse cancers and several autoimmune disorders. EBV predominantly establishes latent infection in B cells and can promote B cell malignancies through functions of well-characterized latent oncoproteins. Aspects of the viral lytic cycle also clearly contribute to EBV-associated diseases, although pathologic roles of lytic reactivation are incompletely understood. Here we use single-cell techniques to examine cellular responses to EBV lytic reactivation in multiple B cell models. Consistent with prior studies, reactivation from latency is incomplete (abortive) in some cells and successful in others. Abortive and full lytic trajectories exhibit distinct biological responses that each may promote pathogenesis and reinforce bimodal latent-lytic control. Intriguingly, a portion on cells that proceed through the lytic cycle exhibits unexpected and striking expression of genes associated with cellular reprogramming, pluripotency, and self-renewal. Collectively, this study provides a valuable resource to understand diverse host-virus dynamics and fates during viral reactivation and identifies multiple modes of EBV lytic pathogenesis to investigate in future research. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE. [Display omitted] • Neoself-antigens are presented on MHC-II at low levels of the invariant chain • Lupus-like disease developed upon deletion of the invariant chain from adult mice • Clonal expansion of neoself-reactive T cells was found in SLE patients • Epstein-Barr virus reactivation is one of the factors for neoself-antigen presentation The discrimination of self- and neoself-antigens by T cells plays a crucial role in the activation of autoreactive T cells, leading to the development of autoimmunity. The reactivation of the Epstein-Barr virus is a possible factor that causes MHC class II molecules to present neoself-antigens by decreasing the expression of the invariant chain. [ABSTRACT FROM AUTHOR]

Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to < 1 × 104 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT. [ABSTRACT FROM AUTHOR]

Published studies have generated compelling results indicating that type I IFN modulates function of HSV-1 latency-associated transcript (LAT). One member of type I IFN is IFNα2A also called Roferon-A). IFNα2A has been used in monotherapy or in combination therapy with other drugs to treat viral infections and different kinds of cancer in humans. The goal of this study was to determine whether the absence of IFNα2A affects primary and latent infections in ocularly infected mice. Therefore, we generated a mouse strain lacking IFNα2A expression (IFNα2A-/-). Ocular HSV-1 replication, IFN and immune cell expressions on days 3 and 5 post infection (PI), as well as eye disease, survival, latency-reactivation, and T cell exhaustion were evaluated in ocularly infected IFNα2A-/- and wild type (WT) control mice. Absence of IFNα2A did not affect other members of the IFNα family but it affected IFNβ and IFNγ expressions as well as some immune cells on day 5 PI compared to WT mice. Viral replication in the eye, eye disease, and survival amongst ocularly infected IFNα2A-/- mice were similar to that of WT infected mice. The absence of IFNα2A significantly reduced the levels of latency and T cell exhaustion but not time of reactivation compared with control mice. Our results suggest that blocking IFNα2A expression may be a useful tool in reducing latency and the subsequent side effects associated with higher levels of latency. Author summary: Many viruses have evolved strategies to circumvent the IFN system, including (i) inhibition of IFN production; (ii) blocking of downstream signaling events that occur after cytokine-receptor binding; and (iii) inhibition of the functions of proteins, which are induced by IFN, including apoptotic proteins. The interferons (IFNs) are of considerable interest in the control of HSV-1 infection due to their rapid generation in response to viral infection and their antiviral activities. Type I interferons, which includes interferon alpha (IFNα), are a family of cytokines important for control of viral infections. There are at least 14 IFNα genes in mouse, amongst which includes the gene encoding IFNα2A that play an important role in human studies. The mechanisms by which HSV-1 interferes with type I IFN responses during primary infection, establishment of latency and reactivation are not fully understood. Thus, to evaluate the importance of IFNα2A on HSV-1 infectivity, we generated IFNα2A knockout mice. The absence of IFNα2A significantly reduced latency and T cell exhaustion, but not virus reactivation. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the deadliest brain cancers with a median survival of only 15 months. This poor prognosis has prompted exploration of novel therapeutic targets for GBM patients. Human cytomegalovirus (HCMV) has been implicated in GBM; however, its impact remains poorly defined, and there is conflicting data over the presence of HCMV in tumors. Nonetheless, clinical trials targeting HCMV have shown promising initial data, and evidence suggests that HCMV may negatively impact GBM patient survival by multiple mechanisms including changes in GBM cell behavior and the tumor microenvironment (TME) that potentiate tumor progression as well as therapy-induced virus reactivation. Moreover, HCMV has many effects on host immunity that could impact tumor behavior by altering the TME, which are largely unexplored. The goal of this review is to describe these potential interactions between HCMV and GBM. Better understanding of these processes may allow the development of new therapeutic modalities to improve GBM patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Currently, evidence regarding the causal relationship between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome is limited and inconsistent. Therefore, this study employs Mendelian randomization (MR) methodology to investigate the causal relationship between the two. Methods: This study selected 110 single-nucleotide polymorphisms (SNPs) of primary immunodeficiency-related genes as instrumental variables (IVs). Genetic associations of primary immunodeficiency-related genes were derived from recent genome-wide association studies (GWAS) data on human plasma protein levels and circulating immune cells. Data on genes associated with varicella-zoster virus reactivation syndrome were obtained from the GWAS Catalog and FINNGEN database, primarily analyzed using inverse variance weighting (IVW) and sensitivity analysis. Results: Through MR analysis, we identified 9 primary immunodeficiency-related genes causally associated with herpes zoster and its subsequent neuralgia; determined causal associations of 20 primary immunodeficiency-related genes with three vascular lesions (stroke, cerebral aneurysm, giant cell arteritis); revealed causal associations of 10 primary immunodeficiency-related genes with two ocular diseases (retinopathy, keratitis); additionally, three primary immunodeficiency-related genes each were associated with encephalitis, cranial nerve palsy, and gastrointestinal infections. Conclusions: This study discovers a certain association between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome, yet further investigations are warranted to explore the specific mechanisms underlying these connections. [ABSTRACT FROM AUTHOR]

CD80 is the best-known costimulatory molecule for effective T cell functions. Many different reports have summarized the role of CD80 in HSV-1 and its functions in maintaining adaptive immunity, which is the main player in causing herpes stromal keratitis (HSK). To determine the effects of absence or overexpression of CD80 in HSV-1 infection, we infected CD80-/- and WT mice with a recombinant HSV-1 expressing murine CD80 (HSV-CD80) in place of the latency associated transcript (LAT). Parental dLAT2903 virus lacking LAT was used as a control. After infection, critical components of infection like virus replication, eye disease, early cellular infiltrates into the corneas and trigeminal ganglia (TG), latency-reactivation in the infected mice were determined. Our findings reveal that the absence of CD80 in the CD80-/- mice infected with both viruses did not affect the viral titers in the mice eyes or eye disease, but it played a significant role in critical components of HSV-induced immunopathology. The WT mice infected with dLAT2903 virus had significantly higher levels of latency compared with the CD80-/- mice infected with dLAT2903 virus, while levels of latency as determined by gB DNA expression were similar between the WT and CD80-/- mice infected with HSV-CD80 virus. In contrast to the differences in the levels of latency between the infected groups, the absence of CD80 expression in the CD80-/- mice or its overexpression by HSV-CD80 virus did not have any effect on the time of reactivation. Furthermore, the absence of CD80 expression contributed to more inflammation in the CD80-/--infected mice. Overall, this study suggests that in the absence of CD80, inflammation increases, latency is reduced, but reactivation is not affected. Altogether, our study suggests that reduced latency correlated with reduced levels of inflammatory molecules and blocking or reducing expression of CD80 could be used to mitigate the immune responses, therefore controlling HSV-induced infection. [ABSTRACT FROM AUTHOR]

Viruses sense cellular states and environmental signals by recruiting host transcription factors to cis -regulatory elements (CREs) in viral genomes. Viral CREs act as signal integration hubs that impart specificity to viral gene regulation. Viral CREs are highly evolvable due to their high mutation rate and ability to rapidly change sensing mechanisms, affecting infection spread and patient outcomes. Latent viral infections can be treated by targeting viral CREs for reactivation or permanent silencing. To withstand a hostile cellular environment and replicate, viruses must sense, interpret, and respond to many internal and external cues. Retroviruses and DNA viruses can intercept these cues impinging on host transcription factors via cis -regulatory elements (CREs) in viral genomes, allowing them to sense and coordinate context-specific responses to varied signals. Here, we explore the characteristics of viral CREs, the classes of signals and host transcription factors that regulate them, and how this informs outcomes of viral replication, immune evasion, and latency. We propose that viral CREs constitute central hubs for signal integration from multiple pathways and that sequence variation between viral isolates can rapidly rewire sensing mechanisms, contributing to the variability observed in patient outcomes. [ABSTRACT FROM AUTHOR]

Acute retinal necrosis (ARN) as the term suggests is recognized as necrotic inflammation of retina, in contrast to toxoplasma retinochoroiditis where involvement of choroid can be appreciated as choroidal thickening on optical coherence tomography scan during active stage. Secondly, sequelae of ARN, such as chronic anterior uveitis and cystoid macular edema, could be challenging to manage as steroid use in various forms poses a risk of virus reactivation. We present a case of ARN caused by varicella zoster virus with an initial confusing clinical picture with toxoplasma retinochoroiditis, documented with choroidal involvement. The patient also developed a chronic anterior uveitis with macular edema after resolution of ARN which was treated with topical interferon (IFN) alfa 2b therapy with successful outcome. This report supports the recently described choroidal involvement in ARN and suggests topical IFN as a novel treatment in management of chronic macular edema post ARN. [ABSTRACT FROM AUTHOR]

Posttransplantation complications pose a major challenge to the long‐term survival and quality of life of organ transplant recipients. These complications encompass immune‐mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft‐versus‐host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients. [ABSTRACT FROM AUTHOR]

Background: Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. Aims: We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. Methods: In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F < 40) and low fatigue (FACIT-F > 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher's exact test for categorical data. Results: We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288). Conclusions: These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke. [ABSTRACT FROM AUTHOR]

Background: Varicella‐zoster virus (VZV) reactivation is the most common infectious complication in the late posthematopoietic stem cell transplantation (HSCT) period and is reported as 16%–41%. Acyclovir prophylaxis is recommended for at least 1 year after HSCT to prevent VZV infections. However, studies on the most appropriate prophylaxis are ongoing in pediatric patients. Methods: Patients who underwent allogeneic HSCT between January 1, 1996 and January 1, 2020 were retrospectively analyzed to outline the characteristics of VZV reactivation after allogeneic HSCT in pediatric patients using 6 months acyclovir prophylaxis. Results: There were 260 patients and 273 HSCTs. Median age was 10.43 (0.47–18.38), and 56% was male. Median follow‐up was 2325 days (18–7579 days). VZV reactivation occurred in 21.2% (n = 58) at a median of 354 (55–3433) days post‐HSCT. The peak incidence was 6–12 months post‐HSCT (43.1%). Older age at HSCT, female gender, history of varicella infection, lack of varicella vaccination, low lymphocyte, CD4 count, and CD4/CD8 ratio at 9 and 12 months post‐HSCT was found as a significant risk for herpes zoster (HZ) in univariate analysis, whereas history of varicella infection and low CD4/CD8 ratio at 12 months post‐HSCT was an independent risk factor in multivariate analysis. Conclusions: Tailoring acyclovir prophylaxis according to pre‐HCT varicella history, posttransplant CD4 T lymphocyte counts and functions, and ongoing immunosuppression may help to reduce HZ‐related morbidity and mortality. [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF), usually precipitated by alcohol misuse or viral reactivation, is characterised by rapid onset and usually reversible liver failure. Various definitions of ACLF have been proposed and widely used across the globe, including those by APASL, COSSH, EASL-CLIF, Japanese experts, and NACSELD. Although all the definitions have several similarities and connote high short-term mortality, a clear and standardised definition is still lacking, hampering research in this key area. In this review, we discuss the similarities and differences among various definitions and propose steps to harmonise EASL-CLIF, APASL, NACSELD, Japanese, and Chinese definitions of ACLF. [ABSTRACT FROM AUTHOR]

Introduction: The risk of infections associated with biological drugs (BD) and Janus kinase inhibitors (JAKi) has been extensively explored in the literature. However, there is a dearth of studies that evaluate both pharmacological groups together and, furthermore, compare them. Here, we review the risk of infections associated with BD and JAKi used in dermatology. Methods: A narrative review was performed. All relevant articles evaluating the risk of infection and opportunistic infections with BD and JAKi between January 2010 and February 2024 were selected. Results: Overall, the incidence of infections, serious infections, and opportunistic infections associated with BD and JAKi is low, but higher than in the general population. JAKi approved for dermatological disorders (abrocitinib, baricitinib, deucravacitinib, upadacitinib, ritlecitinib, and topical ruxolitinib) have been shown to be safe, and present a low rate of infections. We found an elevated risk, especially with anti-tumor necrosis factor (anti-TNF) agents, rituximab, and JAKi (particularly tofacitinib at high doses). Specific associations with infections include tuberculosis and tuberculosis reactivation with anti-TNF agents and tocilizumab; candidiasis with anti-interleukin (IL) 17 agents; hepatitis B virus reactivation with rituximab, anti-TNF, and JAKi; and herpes simplex and herpes zoster infections with JAKi (especially tofacitinib and upadacitinib at high doses). The incidence of infections with ustekinumab and anti-IL-23 was very low. Anti-IL-1, nemolizumab, tralokinumab, and omalizumab were not associated with an increased risk of infections. Dupilumab could decrease the incidence of cutaneous infections. Conclusions: Anti-TNF agents, rituximab, and JAKi (particularly tofacitinib) can increase the risk of infections. Close monitoring of patients undergoing these therapies is recommended. Prospective studies with long-term follow-up are needed to comparatively evaluate the risks of infection deriving from treatment with BD and JAKi. [ABSTRACT FROM AUTHOR]

A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma (KS) is an angio‐proliferative disease with a viral etiology and a multifactorial pathogenesis that results from immune dysfunction. In patients affected by latent viral infections such as herpesviruses, SARS‐CoV‐2 infection may result in lytic cycle reactivation in host cells. A robust immune system response is crucial for eliminating pathogens and resolving both latent and non‐latent viral infections. We report a case series of KS characterized by tumor progression after SARS‐CoV‐2 infection. We performed a systematic literature review of the PubMed/MEDLINE and EMBASE databases. The keyword terms included "SARS‐CoV‐2," "HHV‐8," "Kaposi's sarcoma," "IL‐6," and "COVID‐19." English language restriction was applied. Items not covered by our study were excluded. KS is a complex disease linked to an impaired immune system. Conditions that result in temporary or permanent immunodeficiency can trigger viral reactivation or exacerbate an existing disease. It is feasible that the increase in cytokine levels in COVID‐19 patients, coupled with lymphocyte downregulation and treatment that induces herpesvirus lytic reactivation, may contribute to the progression of KS after SARS‐CoV‐2 infection. These observations suggest that patients with KS should be clinically monitored both during and after SARS‐CoV‐2 infection. Nevertheless, prospective data should be collected to validate this hypothesis and enhance our understanding of the mechanisms implicated in the onset or progression of KS. [ABSTRACT FROM AUTHOR]

Background: Viral reactivations are frequent in hematologial patients due to their cancer‐related and drug‐induced immunosuppressive status. Daratumumab, an anti‐CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, and causes immunosuppression by targeting CD38‐expressing normal lymphocytes. In this single‐center two‐arm real‐life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation in MM patients treated with daratumumab‐based regimens as first‐ or second‐line therapy. Methods: A total of 101 consecutive MM patients were included in this study and were divided into two cohorts: daratumumab and nondaratumumab‐based (control) regimens. Patients treated with >2 lines of therapies were excluded to reduce the confounding factor of multi‐treated cases. Primary endpoint was the CMV reactivation rate. Results: CMV reactivation rate was significantly higher in the daratumumab cohort compared to control group (33% vs. 4%; p < 0.001), also with higher CMV‐DNA levels (>1000 UI/mL in 12% of cases; p < 0.05). However, only one subject developed a CMV disease with severe pneumonia, while 12% of patients were successfully treated with preemptive therapy with valganciclovir. No subjects in the control cohort required anti‐CMV agents (p = 0.02). Conclusion: Our single‐center retrospective experience showed that daratumumab might significantly increase the risk of CMV reactivation in MM, while currently underestimated and related to morbility and mortality in MM patients under treatments. However, further validation on larger and prospective clinical trials are required. [ABSTRACT FROM AUTHOR]

ObjectivesMethodsResultsDiscussionConclusionCochlear implantation (CI) is a surgical intervention used to rehabilitate hearing in individuals, both pediatric and adult, with severe hearing loss. It is generally a safe procedure with rare postoperative complications. Facial nerve paralysis following cochlear implant surgery poses challenges in diagnosis and treatment.This case report details a 48-year-old male who experienced delayed facial paralysis after cochlear implantation, an uncommon occurrence with limited documentation.The facial nerve palsy of the patient resolved by the third week with combined therapy.The etiology of this complication is not fully understood, with latent virus reactivation, particularly HSV and VZV, hypothesized as a probable cause.Successful management involves a combination of corticosteroids, antiviral therapy, and antibiotics, leading to a favorable outcome. [ABSTRACT FROM AUTHOR]

The presence of chronic liver diseases such as metabolic dysfunction-associated steatosis liver disease, viral hepatitis, and cirrhosis may affect the treatment plan in patients with rheumatologic disorders, with concern about the adverse effects of the rheumatic medications on the course of liver disease. Advanced liver disease can change the elimination and activation of many drugs. In addition, there are concerns about the risk of viral reactivation after using biologics and immunosuppressants in patients with chronic viral hepatitis. This narrative review will assess the considerations that should be made before starting the most frequently used drugs in all common rheumatic diseases and patients with chronic liver diseases including chronic viral hepatitis. [ABSTRACT FROM AUTHOR]

The BK polyomavirus (BKPyV) is a small DNA non-enveloped virus whose infection is asymptomatic in most of the world's adult population. However, in cases of immunosuppression, the reactivation of the virus can cause various complications, and in particular, nephropathies in kidney transplant recipients or hemorrhagic cystitis in bone marrow transplant recipients. Recently, it was demonstrated that BKPyV virions can use extracellular vesicles to collectively traffic in and out of cells, thus exiting producing cells without cell lysis and entering target cells by diversified entry routes. By a comparison to other naked viruses, we investigated the possibility that BKPyV virions recruit the Endosomal-Sorting Complexes Required for Transport (ESCRT) machinery through late domains in order to hijack extracellular vesicles. We identified a single potential late domain in the BKPyV structural proteins, a YPX3L motif in the VP1 protein, and used pseudovirions to study the effect of point mutations found in a BKPyV clinical isolate or known to ablate the interaction of such a domain with the ESCRT machinery. Our results suggest that this domain is not involved in BKPyV association with extracellular vesicles but is crucial for capsomere interaction and thus viral particle assembly. [ABSTRACT FROM AUTHOR]

Introduction: Hepatitis B virus reactivation (HBVr) can occur in solid organ transplant (SOT) recipients with previously inactive hepatitis B virus (HBV) infection. Previous studies have reported that HBVr is generally less than 10% in nonliver SOT recipients with past HBV infection. Methods: We conducted a retrospective study from January 2018 to August 2023 at Mayo Clinic sites in Arizona, Florida, and Minnesota. We examined the antiviral prophylaxis strategy used and the characteristics of HBVr in hepatitis B core antibody‐positive (HBcAb +) nonliver SOT adult recipients. Past HBV infection was defined as HBcAb + / hepatitis B surface antigen (HBsAg) –. Chronic HBV infection was defined as HBcAb + / HBsAg +. Results: A total of 180 nonliver SOT recipients were identified during the study period. Indefinite antiviral prophylaxis was utilized in 77 recipients, and none developed HBVr after transplantation. In 103 recipients without antiviral prophylaxis, the incidence of HBVr was 12% (12/97) and 33% (2/6) in those with past HBV infection and chronic HBV infection. The incidence of HBVr in patients with past HBV infection is 16% (8/50), 15% (3/20), and 5% (1/22) in kidney, heart, and lungs, respectively. HBVr was more frequent in those who received alemtuzumab. Among 14 recipients with HBVr, none had HBV‐associated liver failure or death. Conclusions: Our study observed a higher rate of HBVr (12%) in nonliver SOT recipients with past HBV infection compared to the previous studies. Further studies are needed to identify predictors of HBVr in nonliver SOT recipients and optimize antiviral prophylaxis guidance. [ABSTRACT FROM AUTHOR]

Herpes zoster (HZ) is a frequent dermatitis caused by reactivation of the varicella-zoster virus (VZV), previously silent in the dorsal root ganglia of the spinal cord after primary infection. It is more common in adults and the elderly and occasional in children. HZ affecting two dermatomes or HZ duplex (HZD), has a clinical incidence of less than 0.5% and is typically related to an impaired immune response. In particular, it is frequently observed in individuals with malignancies, diabetes, prolonged chemotherapy or radiation therapy, high-dose corticosteroid use, and prolonged immunosuppressive therapy. In the current report, 4 cases of HZD are presented in patients immunosuppressed due to other diseases, its pathogenesis is discussed and its risk factors are analyzed, in order to stimulate greater vigilance among dermatologists who manage immunocompromised patients. [ABSTRACT FROM AUTHOR]

Background: The risk of hepatitis B virus (HBV) reactivation remains unclear in people with multiple sclerosis (MS) receiving ocrelizumab. We aimed to assess HBV seroprevalence and reactivation risk in MS patients on ocrelizumab and to evaluate the effectiveness of antiviral prophylaxis against HBV reactivation. Methods: In this single-center, cross-sectional study, 400 people with MS receiving ocrelizumab were screened for HBV at baseline and antiviral prophylaxis was implemented based on serological results. Patients were monitored for HBV reactivation, and outcomes were analyzed. Results: Among 56 (14%) patients who had serology compatible with occult or resolved HBV infection, 49 (85.7%) received antiviral prophylaxis regularly and had no HBV reactivation during the follow-up. Reactivation of HBV occurred in 2 out of 7 (28.6%) patients who did not receive antiviral prophylaxis and in one patient who did not adhere to the prophylaxis regimen. All patients with reactivation had anti-HBs levels below 100 mIU/mL and the median titer was significantly lower than the patients with no HBV reactivation (p = 0.034). Conclusion: This study highlights a 14% anti-HBc positivity, indicating a potential risk for HBV reactivation in people with MS receiving ocrelizumab. This suggests the importance of vigilant monitoring and the implementation of prophylactic measures. Our recommendation emphasizes antiviral prophylaxis, particularly for patients with low anti-HBs, and a pre-emptive strategy for others. [ABSTRACT FROM AUTHOR]

Solid organ transplant (SOT) recipients are at significant risk of hepatitis B (HB) virus (HBV) reactivation (HBVr). Despite the clinical significance of HBVr after solid organ transplantation, data on the risk factors for HBVr and vaccine effectiveness in SOT recipients with resolved HBV infection are limited. This study evaluated the risk factors for HBVr and the seroconversion rates after HBV vaccination in SOT recipients. Patients who had undergone solid organ transplantation and those with a resolved HBV infection were identified. We matched patients who experienced post-transplantation HBVr with those who did not. We also explored the characteristics and seroconversion rates of HBV-vaccinated patients following transplantation. In total, 1299 SOT recipients were identified as having a resolved HBV infection at the time of transplantation. Thirty-nine patients experienced HBVr. Pre-transplant HB surface antibodies (anti-HBs) positivity and allograft rejection within 3 months after transplantation were independently associated with HBVr. Among the 17 HBV-vaccinated patients, 14 (82.4%) received three or fewer vaccine doses, and 13 (76.5%) had seroconversion with positive anti-HBs results. Pre-transplant anti-HBs(−) status and allograft rejection were risk factors for HBVr in SOT recipients with a resolved HBV infection, and HBV vaccination after transplantation resulted in a high rate of anti-HBs seroconversion. HBV vaccination after transplantation should be considered to reduce the HBVr risk. [ABSTRACT FROM AUTHOR]

Reactivation from latency plays a significant role in maintaining persistent lifelong Epstein-Barr virus (EBV) infection. Mechanisms governing successful activation and progression of the EBV lytic phase are not fully understood. EBV expresses multiple viral microRNAs (miRNAs) and manipulates several cellular miRNAs to support viral infection. To gain insight into the host miRNAs regulating transitions from EBV latency into the lytic stage, we conducted a CRISPR/Cas9-based screen in EBV+ Burkitt lymphoma (BL) cells using anti-Ig antibodies to crosslink the B cell receptor (BCR) and induce reactivation. Using a gRNA library against >1500 annotated human miRNAs, we identified miR-142 as a key regulator of EBV reactivation. Genetic ablation of miR-142 enhanced levels of immediate early and early lytic gene products in infected BL cells. Ago2-PAR-CLIP experiments with reactivated cells revealed miR-142 targets related to Erk/MAPK signaling, including components directly downstream of the B cell receptor (BCR). Consistent with these findings, disruption of miR-142 enhanced SOS1 levels and Mek phosphorylation in response to surface Ig cross-linking. Effects could be rescued by inhibitors of Mek (cobimetinib) or Raf (dabrafenib). Taken together, these results show that miR-142 functionally regulates SOS1/Ras/Raf/Mek/Erk signaling initiated through the BCR and consequently, restricts EBV entry into the lytic cycle. Author summary: Epstein-Barr virus (EBV) is a common herpesvirus that infects most individuals worldwide and can persist in the body for life. Long-term viral persistence is established in part through latently infected memory B cells and periodic reactivation events which maintain viral reservoirs. To investigate functional roles for host non-coding RNAs in EBV latency and reactivation—specifically microRNAs—we conducted a genome-wide CRISPR screen in EBV-positive Burkitt's lymphoma (BL) cells. By screening >1500 human miRNAs, we identified miR-142 as a potent regulator of the lytic cycle. When miR-142 was disrupted, latently infected BL cells responded rapidly to external reactivation triggers and exhibited significantly elevated levels of lytic viral proteins. Through mechanistic studies, we found that miR-142 regulates cell signaling pathways such as the Ras/Raf/Mek/Erk pathway and can target SOS1 encoding a Ras guanine nucleotide exchange factor. Heightened EBV reactivation in miR-142 mutant cells could be reversed using chemical inhibitors to Raf, Mek, or Sos1. These findings provide novel insight into the role of miR-142 in the EBV life cycle and further unveil potential for inhibiting Sos1 as a means to suppress EBV reactivation. [ABSTRACT FROM AUTHOR]

Multiple functions are associated with HSV-1 latency associated transcript (LAT), including establishment of latency, virus reactivation, and antiapoptotic activity. LAT encodes two sncRNAs that are not miRNAs and previously it was shown that they have antiapoptotic activity in vitro. To determine if we can separate the antiapoptotic function of LAT from its latency-reactivation function, we deleted sncRNA1 and sncRNA2 sequences in HSV-1 strain McKrae, creating ΔsncRNA1&2 recombinant virus. Deletion of the sncRNA1&2 in ΔsncRNA1&2 virus was confirmed by complete sequencing of ΔsncRNA1&2 virus and its parental virus. Replication of ΔsncRNA1&2 virus in tissue culture or in the eyes of WT infected mice was similar to that of HSV-1 strain McKrae (LAT-plus) and dLAT2903 (LAT-minus) viruses. The levels of gB DNA in trigeminal ganglia (TG) of mice latently infected with ΔsncRNA1&2 virus was intermediate to that of dLAT2903 and McKrae infected mice, while levels of LAT in TG of latently infected ΔsncRNA1&2 mice was significantly higher than in McKrae infected mice. Similarly, the levels of LAT expression in Neuro-2A cells infected with ΔsncRNA1&2 virus was significantly higher than in McKrae infected cells. Reactivation in TG of ΔsncRNA1&2 infected mice was similar to that of McKrae and time of reactivation in both groups were significantly faster than dLAT2903 infected mice. However, levels of apoptosis in Neuro-2A cells infected with ΔsncRNA1&2 virus was similar to that of dLAT2903 and significantly higher than that of McKrae infected cells. Our results suggest that the antiapoptotic function of LAT resides within the two sncRNAs, which works independently of its latency-reactivation function and it has suppressive effect on LAT expression in vivo and in vitro. Author summary: The LAT region encodes two small non-coding RNAs (LAT sncRNA1 and sncRNA2) and they are expressed in TG of latently infected mice. The sncRNA1 and sncRNA2 are not miRNAs and they can inhibit apoptosis and promote cell survival in vitro. sncRNA1 and sncRNA2 are expressed from the first 1.5-kb of LAT coding sequences and the reactivation and antiapoptotic activity of LAT is within the 1.5 kb of LAT. To determine the role of sncRNA1&2 on latency-reactivation and apoptosis, we constructed a recombinant virus lacking both sncRNA1&2 (i.e., ΔsncRNA1&2). This recombinant virus grow in tissue culture and in the eyes of infected mice similar to that of control viruses. Here we demonstrated a novel function for sncRNA1&2 in reducing antiapoptotic function of LAT and down-regulation of LAT expression in vitro and in vivo. We have also shown that the two sncRNAs encoded within the 1.5 kb of LAT do not play a role in virus reactivation. [ABSTRACT FROM AUTHOR]

Currently, four vaccines for COVID-19 have been licensed by the European Medicines Agency: two viral vector-based vaccines and two mRNA-based vaccines. Since their approval, several cutaneous reactions related to vaccination have been reported in the literature. Among these, viral reactivations are one of the most frequent. The aim of this article was to investigate the current literature regarding viral reactivations following COVID-19 vaccination, focusing attention on pityriasis rosea (PR), herpes zoster and herpes simplex. A comprehensive literature search using various databases was performed and we included metanalyses, reviews, letters to the editor, real-life studies, case series and reports. A total of 48 articles involving 2067 patients were selected. Of these, 32, 6 and 17 articles reported varicella zoster virus (VZV) reactivation (1758 patients), herpes simplex virus (HSV) (238 patients) onset and PR (71 patients), respectively (some articles discussed more than one of these three reactivations). Possible pathogenetic mechanisms underlying viral reactivation are still not understood. Also, the possible correlations between vaccination and viral reactivation should be clarified. Certainly, vaccination should not be discouraged. [ABSTRACT FROM AUTHOR]

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a complex and potentially fatal hypersensitivity condition. We present a unique case report and literature review focusing on DRESS syndrome-associated myocarditis resulting from reactivated viral infections in a 21-year-old female. 3 weeks after 5-day oral co-trimoxazole consumption due to acne, she developed symptoms consistent with DRESS syndrome, including a generalized maculopapular rash. Despite prednisolone treatment, the patient developed fatal fulminant myocarditis linked to HHV-6 and CMV reactivation. The patient's death highlights the importance of early recognition and careful management of DRESS syndrome, especially considering the potential viral reactivation that can lead to severe complications. Postmortem investigations revealed that viral reactivation caused myocarditis. Careful consideration must be given to corticosteroid usage in DRESS treatment, as inappropriate prescribing may promote viral reactivation and subsequent complications. While high-dose corticosteroids initiated within the first week effectively suppress HHV-6 reactivation. Conversely, low-dose or late-start high-dose corticosteroids prove ineffective in preventing HHV-6 viremia. Late- onset or low- dose corticosteroids may lead to fatal complications following the primary viral reactivation. [ABSTRACT FROM AUTHOR]

TRIM32 is often aberrantly expressed in many types of cancers. Kaposi’s sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi’s sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi’s sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers. [ABSTRACT FROM AUTHOR]

Background: The safety of immune‐checkpoint inhibitors (ICIs) has not been thoroughly investigated in non–small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune‐related hepatitis and jaundice in NSCLC patients in a real‐world setting. Methods: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (–)/hepatitis B core antibody immunoglobulin G (anti‐HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (–)/anti‐HBc IgG (–) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune‐related hepatitis, and jaundice. The secondary end points included other immune‐related adverse events and efficacy. Results: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune‐related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune‐related adverse events and efficacy were all comparable among the three groups (p >.05 for all comparisons). Conclusions: In this large, real‐world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal. Hepatitis B virus (HBV) reactivation was observed in patients with chronic hepatitis B without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with occult hepatitis B infection, the risk of HBV reactivation was minimal. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the prevalence and viral reactivations of clinical interest in the immunocompromised patient with particular focus on hematologic and solid organ transplant recipients. Methods: Molecular screening data of CMV, EBV, JCV and BKV from 2011 to 2023 were analyzed. This extensive time span allowed the access to more than 100,000 samples from over 20,000 patients treated at Policlinico Umberto I. It was possible to temporally investigate patient attendance patterns, average age distribution, seasonality of infections, and positivity rates of the analyzed viruses. Results: Between 2019 and 2022 a significant reduction in organ transplants performed and in the positive molecular detection of EBV, JCV and BKV was observed. Additionally, there has been a noteworthy decrease in CMV reactivations, with a reduction of up to 50% starting in 2019. A remarkable reduction of 39% in the rate of CMV viral reactivation has been also achieved in SOT between 2016 and 2023. Conclusion: The years following 2019 were profoundly impacted by the COVID-19 pandemic era. This period resulted in a substantial reduction in healthcare services and hospital visits. Furthermore, the introduction of the drug Letermovir in Italy in 2019 demonstrated remarkable efficacy, evidenced by a reduction in CMV reactivations. Additionally, the adoption of a novel clinical approach centered on personalized therapy facilitated improved management of immunocompromised patients. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case demonstrated the complex pathophysiology of DRESS syndrome presenting with latent human herpes virus infection reactivation due to exposure to sulfasalazine and/or hydroxychloroquine. Patients who do not initially fulfill the diagnostic criteria on admission may evolve and eventually fulfill the criteria. Steroid dose tapering is required to prevent flaring. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming induced by Epstein‐Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV‐associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV‐associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D‐2HG, and serum D‐2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)‐driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α‐KG, which inhibits the expression of EBV lytic genes with CpG‐containing ZREs and the latent‐lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC. [ABSTRACT FROM AUTHOR]

Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression. [ABSTRACT FROM AUTHOR]

The rebound competent viral reservoir (RCVR)–virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped–is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after intravenous challenge with barcoded SIVmac239 as a means to elucidate the dynamics of RCVR establishment in groups of RMs by creating a multi-log range of pre-ART viral loads and then assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of ART after one year. RMs started on ART on days 3, 4, 5, 6, 7, 9 or 12 post-infection showed a nearly 10-fold difference in pre-ART viral measurements for successive ART-initiation timepoints. Only 1 of 8 RMs initiating ART on days 3 and 4 rebounded after ART interruption despite measurable pre-ART plasma viremia. Rebounding plasma from the 1 rebounding RM contained only a single barcode lineage detected at day 50 post-ART. All RMs starting ART on days 5 and 6 rebounded between 14- and 50-days post-ART with 1–2 rebounding variants each. RMs starting ART on days 7, 9, and 12 had similar time-to-measurable plasma rebound kinetics despite multiple log differences in pre-ART plasma viral load (pVL), with all RMs rebounding between 7- and 16-days post-ART with 3–28 rebounding lineages. Calculated reactivation rates per pre-ART pVL were highest for RMs starting ART on days 5, 6, and 7 after which the rate of accumulation of the RCVR markedly decreased for RMs treated on days 9 and 12, consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks post infection. Taken together, these data highlight the heterogeneity of the RCVR between RMs, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection. Author summary: Antiretroviral therapy (ART) stops HIV replication without impacting the "rebound-competent viral reservoir" (RCVR), comprised of persistent, already infected cells that can rekindle active HIV infection once ART is stopped. Despite much effort, the characteristics of the clinically relevant RCVR remain poorly defined. We developed a SIV-infected rhesus macaque model and studied temporal development of the RCVR during primary SIV infection, characterizing the impact of RCVR establishment dynamics on post-ART SIV rebound dynamics. Despite measurable SIV viremia, the viral dissemination that developed up to day 4 of SIV infection was highly labile, unable to form an RCVR that can mediate viral rebound after discontinuation of one year of ART. From days 5 to 7, both the extent of primary infection assessed by plasma viremia and post-ART viral reactivation rates exponentially increased in concert, but from day 7 to 12 post-infection, reactivation rates only marginally increased whereas extent of infection continued exponential expansion. This disconnect suggests that the multiphase establishment of the RCVR is saturable and therefore constitutes only a subset of overall SIV infection when ART is initiated after day 7. These observations have important implications for therapeutic targeting of the RCVR and for measuring the impact of such therapies on RCVR size in vivo. [ABSTRACT FROM AUTHOR]

Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset of memory CD4+ T cells, pose the primary barrier to a cure for HIV-1 infection because they are the source of the viral rebound that almost inevitably follows the interruption of antiretroviral therapy. Over the last 30 years, many of the factors essential for initiating HIV-1 transcription have been identified in studies performed using transformed cell lines, such as the Jurkat T-cell model. However, as highlighted in this review, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP. Furthermore, the central paradox of HIV-1 transcription remains unsolved: how are the initial rounds of transcription achieved in the absence of Tat? A critical limitation of the transformed cell models is that they do not recapitulate the transitions between active effector cells and quiescent memory T cells. Therefore, investigation of the molecular mechanisms of HIV-1 latency reversal and LRA efficacy in a proper physiological context requires the utilization of primary cell models. Recent mechanistic studies of HIV-1 transcription using latently infected cells recovered from donors and ex vivo cellular models of viral latency have demonstrated that the primary blocks to HIV-1 transcription in memory CD4+ T cells are restrictive epigenetic features at the proviral promoter, the cytoplasmic sequestration of key transcription initiation factors such as NFAT and NF-κB, and the vanishingly low expression of the cellular transcription elongation factor P-TEFb. One of the foremost schemes to eliminate the residual reservoir is to deliberately reactivate latent HIV-1 proviruses to enable clearance of persisting latently infected cells—the "Shock and Kill" strategy. For "Shock and Kill" to become efficient, effective, non-toxic latency-reversing agents (LRAs) must be discovered. Since multiple restrictions limit viral reactivation in primary cells, understanding the T-cell signaling mechanisms that are essential for stimulating P-TEFb biogenesis, initiation factor activation, and reversing the proviral epigenetic restrictions have become a prerequisite for the development of more effective LRAs. [ABSTRACT FROM AUTHOR]

Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker–positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up. [ABSTRACT FROM AUTHOR]

Introduction: Hepatitis B virus (HBV) infection is prevalent in Asia including Taiwan. We retrospectively evaluated the risk of HBV reactivation and clinical outcomes in HBV+ and HBV– kidney transplant recipients. Methods: Patients who underwent kidney transplantation between January 2004 and December 2021 were reviewed. The outcomes of interest included risks of HBV reactivation and patient/graft survival. Results: We identified 337 patients (47.5 ± 12 years) in our final cohort. Fifty-two (15.4%) had hepatitis B surface antigen (HBsAg) positive at the time of transplantation. Seventeen developed viral reactivations, with 41.2% of them accompanied by active hepatitis. The graft survival, acute rejection rate, and cancer development after kidney transplantation did not differ in terms of HBsAg status. The Cox multivariate analysis indicated the HBV reactivation risk was increased by a lack of pretransplant anti-HBV medication (hazard ratio [HR], 5.95; 95% confidence interval [CI], 1.31–27.02; p = 0.021) or an absence of lifelong antiviral therapy (HR: 3.14; 95% CI: 1.01–9.74; p = 0.047). Conclusion: Individuals, independent of HBsAg status, had similar prognosis in terms of patient and graft survival, acute rejection rate, and cancer development. The absence of either pretransplant anti-HBV medication or lifelong antiviral therapy was significantly associated with an increased risk of HBV reactivation. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is a prevalent pathogen that establishes life-long latent infection in hematopoietic cells. While this infection is usually asymptomatic, immune dysregulation leads to viral reactivation, which can cause significant morbidity and mortality. However, the mechanisms underpinning reactivation remain incompletely understood. The HCMV major immediate early promoter (MIEP)/enhancer is a key factor in this process, as its transactivation from a repressed to active state helps drive viral gene transcription necessary for reactivation from latency. Numerous host transcription factors bind the MIE locus and recruit repressive chromatin modifiers, thus impeding virus reactivation. One such factor is CCCTC-binding protein (CTCF), a highly conserved host zinc finger protein that mediates chromatin conformation and nuclear architecture. However, the mechanisms by which CTCF contributes to HCMV latency were previously unexplored. Here, we confirm that CTCF binds two convergent sites within the MIE locus during latency in primary CD14+ monocytes, and following cellular differentiation, CTCF association is lost as the virus reactivates. While mutation of the MIE enhancer CTCF binding site does not impact viral lytic growth in fibroblasts, this mutant virus fails to maintain latency in myeloid cells. Furthermore, we show the two convergent CTCF binding sites allow looping to occur across the MIEP, supporting transcriptional repression during latency. Indeed, looping between the two sites diminishes during virus reactivation, concurrent with activation of MIE transcription. Taken together, our data reveal that three-dimensional chromatin looping aids in the regulation of HCMV latency and provides insight into promoter/enhancer regulation that may prove broadly applicable across biological systems. [ABSTRACT FROM AUTHOR]

Purpose: Herpesvirus reactivation has been documented among patients in the intensive care unit (ICU) and is associated with increased morbidity and mortality, particularly for cytomegalovirus (CMV). Epstein–Barr virus (EBV) has been poorly studied despite >95% of the population being seropositive. Our preliminary study suggested an association between EBV reactivation and increased morbidity and mortality. This study aimed to investigate this association among patients admitted to the ICU. Methods: In this multicenter prospective study, polymerase chain reaction was performed to quantify EBV in patients upon ICU admission and then twice a week during their stay. Follow-up was 90 days. Results: The study included 129 patients; 70 (54.3%) had EBV reactivation. On day 90, there was no difference in mortality rates between patients with and without reactivation (25.7% vs 15.3%, p = 0.22). Patients with EBV reactivation at admission had increased mortality compared with those without reactivation and those with later reactivation. EBV reactivation was associated with increased morbidity. Patients with EBV reactivation had fewer ventilator-free days at day 28 than those without reactivation (18 [1–22] vs. 21 days [5–26], p = 0.037) and a higher incidence of acute respiratory distress syndrome (34.3% vs. 17%, p = 0.04), infections (92.9% vs. 78%, p = 0.03), and septic shock (58.6% vs. 32.2%, p = 0.004). More patients with EBV reactivation required renal replacement therapy (30% vs. 11.9%, p = 0.02). EBV reactivation was also associated with a more inflammatory immune profile. Conclusion: While EBV reactivation was not associated with increased 90-day mortality, it was associated with significantly increased morbidity. [ABSTRACT FROM AUTHOR]

Magnesium (Mg) is an essential element that is required as a cofactor for many cellular reactions, including immunologic pathways. The aim of this study was to investigate the potential impact of serum Mg levels on allogeneic hematopoietic stem cell transplantation (alloHSCT) outcomes. Medical records of 340 alloHSCT recipients (median age: 45 [18-71] years; M/F: 210/130) were reviewed for this retrospective study. Serum Mg levels on days -28, -7, 0, +7, +14, +21, +30, +60, and +90 were included in the analysis. Serum Mg +14 levels predicted nonrelapse mortality (NRM) (P =.025) and had a significant impact on the development of mucositis (P =.027), fungal infection (P =.006), engraftment syndrome (P <.001), sinusoidal obstruction syndrome (SOS) (P =.001), cytomegalovirus (CMV) reactivation (P =.039), and acute graft vs host disease (GvHD) (P <.001). Based on the optimal threshold of serum Mg +14 level (1.33 mg/dL; area under the curve: 0.581 [0.515-0.648]; P =.018), the study group was divided into 2 subgroups as low- and high-Mg +14. The incidence of acute GvHD (P =.002), SOS (P =.013), engraftment syndrome (P =.013), CMV reactivation (P =.001), and Epstein Barr virus reactivation (P =.005) was significantly lower in low-Mg +14 group. The probability of overall survival (OS) was significantly better (P =.002), whereas NRM was lower in the low-Mg +14 group (P =.001). Hypomagnesemia seems to provide a considerable advantage for the post-transplant outcome, which may confirm its potential role in the immunologic microenvironment and adaptive immunity. [ABSTRACT FROM AUTHOR]

BK polyomavirus-associated nephropathy (PyVAN) remains a serious threat for renal dysfunction and graft loss in kidney transplant recipients on immunosuppressive medication. In this study, a pilot cohort of 16 kidney transplant recipients were recruited of which eight were with significant BKPV viremia (sBKPV) and the rest were controls matched to age, gender, and time since transplant. We used next-generation sequencing to characterize the miRNA expression profile in urine samples. In total, the expression of 8 miRNAs (miR-16-5p,miR-200c-3p,bkv-miR-B1-3p,let-7b-3p,miR-1269b,bkv-miR-B1-5p,miR-193a-3p,miR-944) were upregulated whereas 21miRNAs (miR-134-5p,miR-4724-5p,miR-127-3p,miR-6500-3p,miR-507,miR-378b,miR-3911,miR-211-5p,miR-486-5p,miR-143-3p,miR-3195,miR-1307-5p,miR-29a-5p,miR-378f,miR-12136,miR-378g,miR-144-3p,miR-378a-3p,let-7i-5p,miR-204-5p,miR-146a-5p) were downregulated with fold change > 2. We found that bkv-miR-B1-5p and bkv-miR-B1-3p have 19-fold and 5-fold higher expression values in BKPV viremia patient samples, respectively. A few earlier studies have reported BKV miRNA in urine and serum samples using the RT- PCR from PyVAN patients. Our results corroborated findings from earlier studies and highlighted the need for additional evaluation of the role of sequencing approaches for monitoring BKPV specific and host miRNAs to better understand the viral reactivation and disease pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) reactivation is a common complication in hepatocellular carcinoma (HCC) patients treated with chemotherapy or immunotherapy. This study aimed to evaluate the risk of HBV reactivation and its effect on survival in HCC patients treated with HAIC and lenvatinib plus PD1s. Methods: We retrospectively collected the data of 213 HBV-related HCC patients who underwent HAIC and lenvatinib plus PD1s treatment between June 2019 to June 2022 at Sun Yat-sen University, China. The primary outcome was the risk of HBV reactivation. The secondary outcomes were overall survival (OS), progression−free survival (PFS), and treatment−related adverse events. Results: Sixteen patients (7.5%) occurred HBV reactivation in our study. The incidence of HBV reactivation was 5% in patients with antiviral prophylaxis and 21.9% in patients without antiviral prophylaxis, respectively. The logistic regression model indicated that for HBV reactivation, lack of antiviral prophylaxis (P=0.003) and tumor diameter (P=0.036) were independent risk factors. The OS and PFS were significantly shorter in the HBV reactivation group than the non-reactivation group (P=0.0023 and P=0.00073, respectively). The number of AEs was more in HBV reactivation group than the non-reactivation group, especially hepatic AEs. Conclusion: HBV reactivation may occur in HCC patients treated with HAIC and lenvatinib plus PD1s. Patients with HBV reactivation had shorter survival time compared with non-reactivation. Therefore, HBV-related HCC patients should undergo antiviral therapy and HBV-DNA monitoring before and during the combination treatment. [ABSTRACT FROM AUTHOR]

HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirm the latency reversal properties of in vivo TGF-β blockade, decrease viral reservoirs and stimulate immune responses. Treatment of eight female, SIV-infected macaques on ART with four 2-weeks cycles of galunisertib leads to viral reactivation as indicated by plasma viral load and immunoPET/CT with a 64Cu-DOTA-F(ab')2-p7D3-probe. Post-galunisertib, lymph nodes, gut and PBMC exhibit lower cell-associated (CA-)SIV DNA and lower intact pro-virus (PBMC). Galunisertib does not lead to systemic increase in inflammatory cytokines. High-dimensional cytometry, bulk, and single-cell (sc)RNAseq reveal a galunisertib-driven shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1. In summary, we demonstrate that galunisertib, a clinical stage TGF-β inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity. Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) induces a unique T cell response, where antigen-specific populations do not contract, but rather inflate during viral latency. It has been proposed that subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells by intermittently engaging T cell receptors (TCRs), but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1 and NFATc2 signal downstream of TCR in mature T lymphocytes. We show selective impacts of NFATc1 and/or NFATc2 genetic ablations on the long-term inflation of MCMV-specific CD8+ T cell responses despite largely maintained responses to acute infection. NFATc1 ablation elicited robust phenotypes in isolation, but the strongest effects were observed when both NFAT genes were missing. CMV control was impaired only when both NFATs were deleted in CD8+ T cells used in adoptive immunotherapy of immunodeficient mice. Transcriptome analyses revealed that T cell intrinsic NFAT is not necessary for CD8+ T cell priming, but rather for their maturation towards effector-memory and in particular the effector cells, which dominate the pool of inflationary cells. Author summary: Cytomegalovirus (CMV) infection is a very common cause of complications in transplant recipients. These patients suffer from opportunistic viruses because their immune system is weakened by immunosuppressive drugs, which are required to avoid transplant rejection by T cells, a key lymphocyte population involved in antiviral defenses. The commonly used immunosuppressive drugs target gene products in a signaling pathway inside T lymphocytes involving two Nuclear Factors of Activated T cells (NFAT) called NFATc1 and NFATc2. We tested the effects of NFAT signaling on T cell responses to CMV in mice lacking either of these genes, or both of them. We show that the T cell responses to CMV are compromised in absence of NFATc1 in a peculiar manner. While early responses upon infection are robust, they are not maintained in the long term. A detailed analysis of these cells showed that cells lacking NFAT display a deficit in T-cell maturation upon the initial activation. Our data may have relevance for the design of future immunosuppressive drugs that may protect patients from organ rejection, while retaining antiviral immune defenses. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) has a lifelong latency period after initial infection. Rarely, however, when the EBV immediate early gene BZLF1 is expressed by a specific stimulus, the virus switches to the lytic cycle to produce progeny viruses. We found that EBV infection reduced levels of various ceramide species in gastric cancer cells. As ceramide is a bioactive lipid implicated in the infection of various viruses, we assessed the effect of ceramide on the EBV lytic cycle. Treatment with C6-ceramide (C6-Cer) induced an increase in the endogenous ceramide pool and increased production of the viral product as well as BZLF1 expression. Treatment with the ceramidase inhibitor ceranib-2 induced EBV lytic replication with an increase in the endogenous ceramide pool. The glucosylceramide synthase inhibitor Genz-123346 inhibited C6-Cer-induced lytic replication. C6-Cer induced extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB phosphorylation, c-JUN expression, and accumulation of the autophagosome marker LC3B. Treatment with MEK1/2 inhibitor U0126, siERK1&2, or siCREB suppressed C6-Cer-induced EBV lytic replication and autophagy initiation. In contrast, siJUN transfection had no impact on BZLF1 expression. The use of 3-methyladenine (3-MA), an inhibitor targeting class III phosphoinositide 3-kinases (PI3Ks) to inhibit autophagy initiation, resulted in reduced beclin-1 expression, along with suppressed C6-Cer-induced BZLF1 expression and LC3B accumulation. Chloroquine, an inhibitor of autophagosome-lysosome fusion, increased BZLF1 protein intensity and LC3B accumulation. However, siLC3B transfection had minimal effect on BZLF1 expression. The results suggest the significance of ceramide-related sphingolipid metabolism in controlling EBV latency, highlighting the potential use of drugs targeting sphingolipid metabolism for treating EBV-positive gastric cancer. IMPORTANCE Epstein-Barr virus remains dormant in the host cell but occasionally switches to the lytic cycle when stimulated. However, the exact molecular mechanism of this lytic induction is not well understood. In this study, we demonstrate that Epstein-Barr virus infection leads to a reduction in ceramide levels. Additionally, the restoration of ceramide levels triggers lytic replication of Epstein-Barr virus with increase in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB. Our study suggests that the Epstein-Barr virus can inhibit lytic replication and remain latent through reduction of host cell ceramide levels. This study reports the regulation of lytic replication by ceramide in Epstein-Barr virus-positive gastric cancer. [ABSTRACT FROM AUTHOR]

Introduction: Long-term space missions trigger a prolonged neuroendocrine stress response leading to immune system dysregulation evidenced by susceptibility to infections, viral reactivation, and skin irritations. However, due to existing technical constraints, real-time functional immune assessments are not currently available to crew inflight. The in vitro cytokine release assay (CRA) has been effectively employed to study the stimulated cytokine response of immune cells in whole blood albeit limited to pre- and post-flight sessions. A novel two-valve reaction tube (RT) has been developed to enable the execution of the CRA on the International Space Station (ISS). Methods: In a comprehensive test campaign, we assessed the suitability of three materials (silicone, C-Flex, and PVC) for the RT design in terms of biochemical compatibility, chemical stability, and final data quality analysis. Furthermore, we thoroughly examined additional quality criteria such as safety, handling, and the frozen storage of antigens within the RTs. The validation of the proposed crew procedure was conducted during a parabolic flight campaign. Results: The selected material and procedure proved to be both feasible and secure yielding consistent and dependable data outcomes. This new hardware allows for the stimulation of blood samples on board the ISS, with subsequent analysis still conducted on the ground. Discussion: The resultant data promises to offer a more accurate understanding of the stress-induced neuroendocrine modulation of immunity during space travel providing valuable insights for the scientific community. Furthermore, the versatile nature of the RT suggests its potential utility as a testing platform for various other assays or sample types. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) reactivation in the setting of immunosuppressive therapy is an increasingly recognized and preventable cause of elevated liver enzymes and clinical hepatitis in treated patients. However, not all immunosuppressive therapies confer the same risk. The purpose of this article was to review the literature on risks of HBV reactivation associated with immunosuppressive agents and propose a management algorithm. We searched Google Scholar, PubMed, and MEDLINE for studies related to hepatitis B reactivation and various immunosuppressive agents. The risk of HBV reactivation was found to differ by agent and depending on whether a patient had chronic HBV (HBsAg+) or past HBV (HBsAg−, anti-HBc+). The highest risk of reactivation (>10%) was associated with anti-CD20 agents and hematopoietic stem cell transplants. Multiple societies recommend HBV-specific anti-viral prophylaxis for patients with positive HBsAg prior to the initiation of immunosuppressive therapy, while the guidance for HBsAg− patients is more variable. Clinicians should check HBV status prior to beginning an immune-suppressive therapy. Patients with positive HBsAg should be initiated on antiviral prophylaxis in the majority of cases, whereas HBsAg− individuals should be evaluated on a case-by-case basis. Further research is required to determine the optimum duration of therapy. [ABSTRACT FROM AUTHOR]

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies. Author summary: Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with several human malignancies. The life cycle of KSHV comprises latency and the lytic phase. The transition from latency to the lytic phase, known as reactivation, is crucial for viral replication and pathogenesis. Previous studies have established that KSHV reactivation is orchestrated by a viral transcription factor, RTA. However, the specific molecular mechanisms governing RTA stability have remained elusive. In this study, we demonstrate that KSHV RTA recruits two host deubiquitinases (DUBs), OTUD4, and USP7, to promote RTA deubiquitination and stabilization, facilitating viral reactivation. Intriguingly, the DUB activity of OTUD4 is dispensable; instead, OTUD4 serves as an adaptor protein that recruits USP7 to deubiquitinate and stabilize RTA. Our study not only unveils the mechanism by which KSHV exploits the OTUD4-USP7 deubiquitinases to enhance lytic reactivation but also provides insights into the development of novel antiviral therapeutic strategies targeting host deubiquitinase complexes. [ABSTRACT FROM AUTHOR]

Background: Entecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection. Methods: This study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery. Discussion: This study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study. Trial registration: ClinicalTrials.gov NCT02650271. Registered on January 7, 2016. [ABSTRACT FROM AUTHOR]