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1.
Vopr Virusol ; 69(2): 134-150, 2024 May 06.
Article in Russian | MEDLINE | ID: mdl-38843020

ABSTRACT

INTRODUCTION: SARS-CoV-2 infection causes immune disorders that create conditions for the reactivation of human herpesviruses (HHVs). However, the estimates of the HHVs effect on the course and outcome of COVID-19 are ambiguous. Аim - to study the possible relationship between the HHV reactivation and the adverse outcome of COVID-19. MATERIALS AND METHODS: Postmortem samples from the brain, liver, spleen, lymph nodes and lungs were obtained from 59 patients treated at the Moscow Infectious Diseases Hospital No.1 in 2021-2023. The group 1 comprised 39 patients with fatal COVID-19; group 2 (comparison group) included 20 patients not infected with SARS-CoV-2 who died from various somatic diseases. HHV DNA and SARS-CoV-2 RNA were determined by PCR. RESULTS: HHV DNA was found in autopsy samples from all patients. In group 1, EBV was most often detected in lymph nodes (94%), HHV-6 in liver (68%), CMV in lymph nodes (18%), HSV in brain (16%), VZV in lung and spleen (3% each). The detection rates of HHVs in both groups was similar. Important differences were found in viral load. In patients with COVID-19, the number of samples containing more than 1,000 copies of HHV DNA per 100,000 cells was 52.4%, in the comparison group - 16.6% (p < 0.002). An association has been established between the reactivation of HSV and HHV-6 and the severity of lung damage. Reactivation of EBV correlated with increased levels of liver enzymes. CONCLUSION: Reactivation of HHVs in patients with fatal COVID-19 was associated with severe lung and liver damages, which indicates a link between HHV reactivation and COVID-19 deaths.


Subject(s)
Autopsy , COVID-19 , DNA, Viral , Herpesviridae Infections , Herpesviridae , SARS-CoV-2 , Humans , COVID-19/virology , COVID-19/mortality , COVID-19/diagnosis , COVID-19/pathology , Female , Male , DNA, Viral/genetics , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Middle Aged , Aged , Herpesviridae/genetics , Herpesviridae/isolation & purification , Herpesviridae Infections/virology , Herpesviridae Infections/mortality , Adult , Lung/virology , Lung/pathology , Virus Activation , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/isolation & purification , Moscow , Viral Load , Lymph Nodes/virology , Lymph Nodes/pathology , Aged, 80 and over , Spleen/virology , Spleen/pathology
2.
Ter Arkh ; 96(5): 523-530, 2024 Jun 03.
Article in Russian | MEDLINE | ID: mdl-38829815

ABSTRACT

Patients with rheumatic diseases infected with hepatitis B virus (HBV) are difficult to manage not only due to the presence of risk factors for the development and rapid progression of liver cirrhosis, but also due to the likelihood of reactivation of this infection. Despite the successes achieved in the fight against HBV, the virus cannot be completely defeated due to the presence of hidden forms of the disease, escaping the field of vision of a rheumatologist and an infectionist. Based on the results of the analysis of current publications, the paper presents the rationale for a complete immunological screening of patients with rheumatic diseases when prescribing antirheumatic therapy. The issues of the role of COVID-19 in the exacerbation of chronic viral hepatitis B, antiviral prevention and monitoring are discussed, the classification of antirheumatic drugs according to the risk of HBV reactivation is presented.


Subject(s)
COVID-19 , Hepatitis B, Chronic , Rheumatic Diseases , Virus Activation , Humans , Rheumatic Diseases/drug therapy , Rheumatic Diseases/complications , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/diagnosis , COVID-19/epidemiology , Antirheumatic Agents , Hepatitis B virus , Mass Screening/methods , Antiviral Agents/therapeutic use , SARS-CoV-2 , Risk Factors
3.
Methods Mol Biol ; 2807: 45-59, 2024.
Article in English | MEDLINE | ID: mdl-38743220

ABSTRACT

Latent HIV-1 reservoirs are a major obstacle to the eradication of HIV-1. Several cure strategies have been proposed to eliminate latent reservoirs. One of the key strategies involves the reactivation of latent HIV-1 from cells using latency-reversing agents. However, currently it is unclear whether any of the latency-reversing agents are able to completely reactivate HIV-1 provirus transcription in all latent cells. An understanding of the reactivation of HIV-1 provirus at single-cell single-molecule level is necessary to fully comprehend the reactivation of HIV-1 in the reservoirs. Furthermore, since reactivable viruses in the pool of latent reservoirs are rare, combining single-cell imaging techniques with the ability to visualize a large number of reactivated single cells that express both viral RNA and proteins in a pool of uninfected and non-reactivated cells will provide unprecedented information about cell-to-cell variability in reactivation. Here, we describe the single-cell single-molecule RNA-FISH (smRNA-FISH) method to visualize HIV-1 gag RNA combined with the immunofluorescence (IF) method to detect Gag protein to characterize the reactivated cells. This method allows the visualization of subcellular localization of RNA and proteins before and after reactivation and facilitates absolute quantitation of the number of transcripts per cell using FISH-quant. In addition, we describe a high-speed and high-resolution scanning (HSHRS) fluorescence microscopy imaging method to visualize rare and reactivated cells in a pool of non-reactivated cells with high efficiency.


Subject(s)
Fluorescent Antibody Technique , HIV-1 , In Situ Hybridization, Fluorescence , RNA, Viral , Single Molecule Imaging , Single-Cell Analysis , Virus Activation , Virus Latency , HIV-1/physiology , HIV-1/genetics , Humans , In Situ Hybridization, Fluorescence/methods , RNA, Viral/genetics , Single-Cell Analysis/methods , Single Molecule Imaging/methods , Fluorescent Antibody Technique/methods , HIV Infections/virology , Proviruses/genetics
4.
Nat Commun ; 15(1): 4156, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755141

ABSTRACT

Epstein-Barr virus (EBV) uses a biphasic lifecycle of latency and lytic reactivation to infect >95% of adults worldwide. Despite its central role in EBV persistence and oncogenesis, much remains unknown about how EBV latency is maintained. We used a human genome-wide CRISPR/Cas9 screen to identify that the nuclear protein SFPQ was critical for latency. SFPQ supported expression of linker histone H1, which stabilizes nucleosomes and regulates nuclear architecture, but has not been previously implicated in EBV gene regulation. H1 occupied latent EBV genomes, including the immediate early gene BZLF1 promoter. Upon reactivation, SFPQ was sequestered into sub-nuclear puncta, and EBV genomic H1 occupancy diminished. Enforced H1 expression blocked EBV reactivation upon SFPQ knockout, confirming it as necessary downstream of SFPQ. SFPQ knockout triggered reactivation of EBV in B and epithelial cells, as well as of Kaposi's sarcoma-associated herpesvirus in B cells, suggesting a conserved gamma-herpesvirus role. These findings highlight SFPQ as a major regulator of H1 expression and EBV latency.


Subject(s)
Herpesvirus 4, Human , Histones , PTB-Associated Splicing Factor , Virus Activation , Virus Latency , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Humans , Histones/metabolism , Virus Activation/genetics , Virus Latency/genetics , PTB-Associated Splicing Factor/metabolism , PTB-Associated Splicing Factor/genetics , Gene Expression Regulation, Viral , B-Lymphocytes/virology , B-Lymphocytes/metabolism , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/metabolism , CRISPR-Cas Systems , Promoter Regions, Genetic/genetics , Trans-Activators/metabolism , Trans-Activators/genetics , Genome, Viral
5.
J Clin Invest ; 134(9)2024 May 01.
Article in English | MEDLINE | ID: mdl-38690731

ABSTRACT

Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised patients, reactivating virus can cause severe disease. Persistent EBV has been associated with several malignancies in both immunocompromised and nonimmunocompromised persons. Reactivation and shedding occur with most herpesviruses, despite potent virus-specific antibodies and T cell immunity as measured in the blood. The licensure of therapeutic vaccines to reduce zoster indicates that effective therapeutic vaccines for other herpesviruses should be feasible. However, varicella-zoster virus is different from other human herpesviruses in that it is generally only shed during varicella and zoster. Unlike prophylactic vaccines, in which the correlate of immunity is antibody function, T cell immunity is the correlate of immunity for the only effective therapeutic herpesvirus vaccine-zoster vaccine. While most studies of therapeutic vaccines have measured immunity in the blood, cellular immunity at the site of reactivation is likely critical for an effective therapeutic vaccine for certain viruses. This Review summarizes the status of therapeutic vaccines for herpes simplex virus, cytomegalovirus, and Epstein-Barr virus and proposes approaches for future development.


Subject(s)
Herpesvirus Vaccines , Humans , Herpesvirus Vaccines/immunology , Herpesvirus Vaccines/therapeutic use , Herpesviridae Infections/immunology , Herpesviridae Infections/prevention & control , Herpesviridae Infections/virology , Herpesvirus 4, Human/immunology , Animals , Herpesviridae/immunology , Virus Activation/immunology , Cytomegalovirus/immunology
6.
Biol Pharm Bull ; 47(5): 941-945, 2024.
Article in English | MEDLINE | ID: mdl-38735754

ABSTRACT

Hepatitis B virus reactivation (HBV-R) is a serious complication that can occur in patients with resolved HBV infection during cancer chemotherapy. We examined the levels of HBV surface antibody (HBsAb) and HBV core antibody (HBcAb) to assess the incidence of HBV-R in cancer patients including hematopoietic stem cell transplantation (HSCT) and rituximab administration. This retrospective cohort study included 590 patients with resolved HBV infection. The incidence of HBV-R was evaluated 761.5 (range, 90-3898) days after the inititiation of chemotherapy. Of the patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All 13 patients exhibited lower HBsAb (<100 mIU/mL) levels at baseline. A higher level of HBcAb (≥100 cut off index (C.O.I.)) was a possible risk factor for HBV-R as well as HSCT and rituximab administration. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab were at a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results suggest that assessment of HBsAb and HBcAb levels prior to the chemotherapy is important for identifying patients at high risk of HBV-R, especially in solid cancers without HSCT and rituximab administration.


Subject(s)
Hepatitis B Antibodies , Hepatitis B Surface Antigens , Hepatitis B virus , Hepatitis B , Rituximab , Virus Activation , Humans , Male , Female , Middle Aged , Retrospective Studies , Hepatitis B Antibodies/blood , Hepatitis B Antibodies/immunology , Hepatitis B virus/immunology , Hepatitis B virus/physiology , Virus Activation/drug effects , Rituximab/therapeutic use , Rituximab/adverse effects , Adult , Aged , Hepatitis B/immunology , Hepatitis B Surface Antigens/blood , Hepatitis B Surface Antigens/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Young Adult , Neoplasms/drug therapy , Neoplasms/immunology , Hepatitis B Core Antigens/immunology , Hepatitis B Core Antigens/blood , Aged, 80 and over , Adolescent
7.
J Int Med Res ; 52(5): 3000605241252580, 2024 May.
Article in English | MEDLINE | ID: mdl-38760056

ABSTRACT

Recombinant human type II tumour necrosis factor receptor-antibody fusion protein (rh TNFR:Fc) is an immunosuppressant approved for treating rheumatoid arthritis (RA). This case report describes a case of hepatitis B reactivation in a patient with drug-induced acute-on-chronic liver failure. A 58-year-old woman with a history of RA was treated with rh TNFR:Fc; and then subsequently received 25 mg rh TNFR:Fc, twice a week, as maintenance therapy. No anti-hepatitis B virus (HBV) preventive treatment was administered. Six months later, she was hospitalized with acute jaundice. HBV reactivation was observed, leading to acute-on-chronic liver failure. After active treatment, the patient's condition improved and she recovered well. Following careful diagnosis and treatment protocols are essential when treating RA with rh TNFR:Fc, especially in anti-hepatitis B core antigen antibody-positive patients, even when the HBV surface antigen and the HBV DNA are negative. In the case of HBV reactivation, liver function parameters, HBV surface antigen and HBV DNA should be closely monitored during treatment, and antiviral drugs should be used prophylactically when necessary, as fatal hepatitis B reactivation may occur in rare cases. A comprehensive evaluation and medication should be administered in a timely manner after evaluating the patient's physical condition and closely monitoring the patient.


Subject(s)
Hepatitis B virus , Hepatitis B , Recombinant Fusion Proteins , Virus Activation , Humans , Female , Middle Aged , Hepatitis B virus/pathogenicity , Hepatitis B virus/physiology , Virus Activation/drug effects , Recombinant Fusion Proteins/therapeutic use , Hepatitis B/virology , Hepatitis B/drug therapy , Hepatitis B/complications , Hepatitis B/immunology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/virology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/complications , Liver Failure/virology , Liver Failure/etiology
8.
PLoS One ; 19(5): e0303995, 2024.
Article in English | MEDLINE | ID: mdl-38771836

ABSTRACT

BACKGROUNDS: In critically ill patients with COVID-19, secondary infections are potentially life-threatening complications. This study aimed to determine the prevalence, clinical characteristics, and risk factors of CMV reactivation among critically ill immunocompetent patients with COVID-19 pneumonia. METHODS: A retrospective cohort study was conducted among adult patients who were admitted to ICU and screened for quantitative real-time PCR for CMV viral load in a tertiary-care hospital during the third wave of the COVID-19 outbreak in Thailand. Cox regression models were used to identify significant risk factors for developing CMV reactivation. RESULTS: A total of 185 patients were studied; 133 patients (71.9%) in the non-CMV group and 52 patients (28.1%) in the CMV group. Of all, the mean age was 64.7±13.3 years and 101 patients (54.6%) were males. The CMV group had received a significantly higher median cumulative dose of corticosteroids than the non-CMV group (301 vs 177 mg of dexamethasone, p<0.001). Other modalities of treatments for COVID-19 including anti-viral drugs, anti-cytokine drugs and hemoperfusion were not different between the two groups (p>0.05). The 90-day mortality rate for all patients was 29.1%, with a significant difference between the CMV group and the non-CMV group (42.3% vs. 24.1%, p = 0.014). Median length of stay was longer in the CMV group than non-CMV group (43 vs 24 days, p<0.001). The CMV group has detectable CMV DNA load with a median [IQR] of 4,977 [1,365-14,742] IU/mL and 24,570 [3,703-106,642] in plasma and bronchoalveolar fluid, respectively. In multivariate analysis, only a cumulative corticosteroids dose of dexamethasone ≥250 mg (HR = 2.042; 95%CI, 1.130-3.688; p = 0.018) was associated with developing CMV reactivation. CONCLUSION: In critically ill COVID-19 patients, CMV reactivation is frequent and a high cumulative corticosteroids dose is a significant risk factor for CMV reactivation, which is associated with poor outcomes. Further prospective studies are warranted to determine optimal management.


Subject(s)
COVID-19 , Critical Illness , Cytomegalovirus Infections , Cytomegalovirus , Humans , Male , Middle Aged , COVID-19/epidemiology , COVID-19/virology , COVID-19/complications , Female , Cytomegalovirus Infections/epidemiology , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/virology , Cytomegalovirus Infections/complications , Risk Factors , Aged , Cytomegalovirus/physiology , Cytomegalovirus/drug effects , Cytomegalovirus/isolation & purification , Retrospective Studies , Prevalence , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Virus Activation/drug effects , Thailand/epidemiology , Viral Load
9.
Nat Commun ; 15(1): 3729, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702330

ABSTRACT

The unique virus-cell interaction in Epstein-Barr virus (EBV)-associated malignancies implies targeting the viral latent-lytic switch is a promising therapeutic strategy. However, the lack of specific and efficient therapeutic agents to induce lytic cycle in these cancers is a major challenge facing clinical implementation. We develop a synthetic transcriptional activator that specifically activates endogenous BZLF1 and efficiently induces lytic reactivation in EBV-positive cancer cells. A lipid nanoparticle encapsulating nucleoside-modified mRNA which encodes a BZLF1-specific transcriptional activator (mTZ3-LNP) is synthesized for EBV-targeted therapy. Compared with conventional chemical inducers, mTZ3-LNP more efficiently activates EBV lytic gene expression in EBV-associated epithelial cancers. Here we show the potency and safety of treatment with mTZ3-LNP to suppress tumor growth in EBV-positive cancer models. The combination of mTZ3-LNP and ganciclovir yields highly selective cytotoxic effects of mRNA-based lytic induction therapy against EBV-positive tumor cells, indicating the potential of mRNA nanomedicine in the treatment of EBV-associated epithelial cancers.


Subject(s)
Epstein-Barr Virus Infections , Herpesvirus 4, Human , Liposomes , Nanoparticles , Trans-Activators , Humans , Herpesvirus 4, Human/genetics , Trans-Activators/metabolism , Trans-Activators/genetics , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/drug therapy , Animals , Nanoparticles/chemistry , Cell Line, Tumor , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Virus Activation/drug effects , Xenograft Model Antitumor Assays , Gene Expression Regulation, Viral/drug effects , Mice, Nude , Female
11.
World J Gastroenterol ; 30(10): 1295-1312, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38596493

ABSTRACT

Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.


Subject(s)
Hepatitis B, Chronic , Hepatitis B , Liver Neoplasms , Humans , Hepatitis B virus , Hepatitis B/drug therapy , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/pharmacology , Liver Neoplasms/drug therapy , Antiviral Agents/pharmacology , Disease Progression , Virus Activation , Hepatitis B Surface Antigens , Hepatitis B, Chronic/drug therapy
12.
World J Gastroenterol ; 30(9): 1253-1256, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38577192

ABSTRACT

Hepatitis B virus (HBV) reactivation (HBVr) represents a severe and potentially life-threatening condition, and preventive measures are available through blood test screening or prophylactic therapy administration. The assessment of HBVr traditionally considers factors such as HBV profile, including hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen, along with type of medication (chemotherapy; immunomodulants). Nevertheless, consideration of possible patient's underlying tumor and the specific malignancy type (solid or hematologic) plays a crucial role and needs to be assessed for decision-making process.


Subject(s)
Hepatitis B , Neoplasms , Humans , Hepatitis B virus , Virus Activation , Hepatitis B Surface Antigens , Neoplasms/drug therapy , Hepatitis B/diagnosis , Hepatitis B/drug therapy , Antiviral Agents/adverse effects
13.
J Med Virol ; 96(5): e29634, 2024 May.
Article in English | MEDLINE | ID: mdl-38682578

ABSTRACT

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.


Subject(s)
DNA Methylation , Epstein-Barr Virus Infections , Herpesvirus 4, Human , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Virus Activation , Humans , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/virology , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/complications , Viral Matrix Proteins/metabolism , Viral Matrix Proteins/genetics , Epigenesis, Genetic , Disease Progression
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 561-567, 2024 Apr.
Article in Chinese | MEDLINE | ID: mdl-38660867

ABSTRACT

OBJECTIVE: To explore the clinical characteristics and risk factors of cytomegalovirus(CMV) and Epstein-Barr virus(EBV) co-reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its influence on prognosis. METHODS: The clinical data of 222 patients who received allo-HSCT from January 2015 to December 2020 were collected, and the patients were divided into groups according to the occurrence of CMV and EBV infection. Kaplan-Meier method was used for survival analysis, and Cox proportional hazard regression model was used to analyze the risk factors of co-reactivation of CMV and EBV. RESULTS: After allo-HSCT, there were 30 patients with co-reactivation of CMV and EBV (CMV++EBV+ group), 101 patients with CMV viremia (CMV+ group), 149 patients with EBV viremia (EBV+ group), and 28 patients with CMV and EBV inactivation (CMV-+ EBV- group). Compared with the other groups, the incidence of acute graft-versus-host disease (aGVHD) and hemorrhagic cystitis (HC) was higher in CMV++ EBV+ groups (53.3% vs 42.6%, 36.9%, 17.9%, P < 0.001; 36.7% vs 32.7%, 22.8%, 10.7%, P =0.042). The incidence of post-transplant lymphoproliferative disease (PTLD) in CMV++ EBV+ group was similar to CMV+ group and EBV+ group (3.3% vs 3.0%, 3.4%, P =0.811). Univariate and multivariate analysis showed that the persistent time of CMV and EBV after transplantation were independent risk factors for co-reactivation of CMV and EBV. Compared with the other groups, the 2-year overall survival (OS) rate and 2-year disease-free survival (DFS) rate of patients in CMV++EBV+ group were lower (46.7% vs 74.9%, 83.4%, 71.4%, P < 0.001; 46.7% vs 70.9%, 79.5%, 69.9%, P =0.002), and 2-year non-recurrence mortality (NRM) was higher (48.2% vs 22%, 13.6%, 18.7%, P <0.001). CONCLUSION: The persistent time of CMV and EBV after transplantation are independent risk factors for patients with co-reactivation of CMV and EBV. Patients with co-reactivation of CMV and EBV had lower OS and DFS rate and higher NRM, suggesting that the clinical prognosis of the patients are worse.


Subject(s)
Cytomegalovirus Infections , Cytomegalovirus , Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Herpesvirus 4, Human , Transplantation, Homologous , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Risk Factors , Graft vs Host Disease , Prognosis , Virus Activation , Female , Male , Viremia
15.
Rev Med Virol ; 34(3): e2538, 2024 May.
Article in English | MEDLINE | ID: mdl-38658176

ABSTRACT

Serious adverse events following vaccination include medical complications that require hospitalisation. The live varicella vaccine that was approved by the Food and Drug Administration in the United States in 1995 has an excellent safety record. Since the vaccine is a live virus, adverse events are more common in immunocompromised children who are vaccinated inadvertently. This review includes only serious adverse events in children considered to be immunocompetent. The serious adverse event called varicella vaccine meningitis was first reported in a hospitalised immunocompetent child in 2008. When we carried out a literature search, we found 15 cases of immunocompetent children and adolescents with varicella vaccine meningitis; the median age was 11 years. Eight of the children had received two varicella vaccinations. Most of the children also had a concomitant herpes zoster rash, although three did not. The children lived in the United States, Greece, Germany, Switzerland, and Japan. During our literature search, we found five additional cases of serious neurological events in immunocompetent children; these included 4 cases of progressive herpes zoster and one case of acute retinitis. Pulses of enteral corticosteroids as well as a lack of herpes simplex virus antibody may be risk factors for reactivation in immunocompetent children. All 20 children with adverse events were treated with acyclovir and recovered; 19 were hospitalised and one child was managed as an outpatient. Even though the number of neurological adverse events remains exceedingly low following varicella vaccination, we recommend documentation of those caused by the vaccine virus.


Subject(s)
Chickenpox Vaccine , Meningitis, Viral , Adolescent , Child , Child, Preschool , Female , Humans , Male , Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , Chickenpox/prevention & control , Chickenpox/virology , Chickenpox Vaccine/administration & dosage , Chickenpox Vaccine/adverse effects , Chickenpox Vaccine/immunology , Herpesvirus 3, Human/immunology , Meningitis, Viral/virology , Nervous System Diseases/virology , Nervous System Diseases/etiology , Vaccination/adverse effects , Virus Activation/drug effects
16.
Proc Natl Acad Sci U S A ; 121(19): e2313823121, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38683980

ABSTRACT

HIV latency regulation in monocytes and macrophages can vary according to signals directing differentiation, polarization, and function. To investigate these processes, we generated an HIV latency model in THP-1 monocytes and showed differential levels of HIV reactivation among clonal populations. Monocyte-to-macrophage differentiation of HIV-infected primary human CD14+ and THP-1 cells induced HIV reactivation and showed that virus production increased concomitant with macrophage differentiation. We applied the HIV-infected THP-1 monocyte-to-macrophage (MLat) model to assess the biological mechanisms regulating HIV latency dynamics during monocyte-to-macrophage differentiation. We pinpointed protein kinase C signaling pathway activation and Cyclin T1 upregulation as inherent differentiation mechanisms that regulate HIV latency reactivation. Macrophage polarization regulated latency, revealing proinflammatory M1 macrophages suppressed HIV reactivation while anti-inflammatory M2 macrophages promoted HIV reactivation. Because macrophages rely on reactive-oxygen species (ROS) to exert numerous cellular functions, we disrupted redox pathways and found that inhibitors of the thioredoxin (Trx) system acted as latency-promoting agents in T-cells and monocytes, but opposingly acted as latency-reversing agents in macrophages. We explored this mechanism with Auranofin, a clinical candidate for reducing HIV reservoirs, and demonstrated Trx reductase inhibition led to ROS induced NF-κB activity, which promoted HIV reactivation in macrophages, but not in T-cells and monocytes. Collectively, cell type-specific differences in HIV latency regulation could pose a barrier to HIV eradication strategies.


Subject(s)
Cell Differentiation , HIV Infections , HIV-1 , Homeostasis , Macrophages , Monocytes , Oxidation-Reduction , Reactive Oxygen Species , Virus Activation , Virus Latency , Humans , Virus Latency/physiology , Macrophages/virology , Macrophages/metabolism , Monocytes/virology , Monocytes/metabolism , HIV-1/physiology , HIV Infections/virology , HIV Infections/metabolism , Virus Activation/physiology , Reactive Oxygen Species/metabolism , THP-1 Cells , Signal Transduction , Protein Kinase C/metabolism
17.
Viruses ; 16(4)2024 03 24.
Article in English | MEDLINE | ID: mdl-38675841

ABSTRACT

HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease-this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations.


Subject(s)
Hematopoietic Stem Cell Transplantation , Herpesvirus 6, Human , Receptors, Chimeric Antigen , Roseolovirus Infections , Virus Activation , Herpesvirus 6, Human/immunology , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/physiology , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Roseolovirus Infections/virology , Roseolovirus Infections/immunology , Roseolovirus Infections/therapy , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/genetics , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/adverse effects , Graft vs Host Disease/immunology , Graft vs Host Disease/etiology
18.
Clin J Gastroenterol ; 17(3): 505-510, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38587568

ABSTRACT

Hepatitis C virus (HCV) reactivation has been reported to be caused due to several anticancer drugs and immunosuppressive agents; however, HCV reactivation after steroid monotherapy has rarely been reported. Here, we report the case of a 65-year-old Japanese man with HCV infection who developed HCV reactivation after the administration of prednisolone (PSL) for 6 days for sudden deafness. In the patient history, the positivity for anti-HCV antibody was observed, but serum level of HCV RNA was not measured. Two months after PSL administration, the patient experienced an alanine aminotransferase (ALT) flare and the serum level of HCV RNA was observed to be 6.2 log IU/mL; then, the patient was admitted to our hospital for hepatitis treatment. Based on the clinical course and laboratory findings, the patient was diagnosed with HCV reactivation. Although the ALT levels decreased spontaneously during follow-up, they did not drop to normal range; subsequently, sofosbuvir and ledipasvir treatments were started. A sustained virological response 24 weeks after the end of treatment was achieved. This case study suggests that HCV reactivation with hepatitis flare can occur even after a steroid monotherapy, and doctors should pay attention to HCV reactivation when administering PSL for patients with HCV infection.


Subject(s)
Antiviral Agents , Hearing Loss, Sudden , Hepacivirus , Prednisolone , Virus Activation , Humans , Male , Aged , Prednisolone/therapeutic use , Hearing Loss, Sudden/drug therapy , Hearing Loss, Sudden/etiology , Hearing Loss, Sudden/virology , Virus Activation/drug effects , Antiviral Agents/therapeutic use , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/complications , Sofosbuvir/therapeutic use , Fluorenes/therapeutic use , Fluorenes/adverse effects , Benzimidazoles/therapeutic use , Benzimidazoles/adverse effects , Alanine Transaminase/blood , RNA, Viral/blood , Glucocorticoids/therapeutic use , Glucocorticoids/adverse effects
19.
PLoS One ; 19(4): e0299198, 2024.
Article in English | MEDLINE | ID: mdl-38635661

ABSTRACT

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.


Subject(s)
Burkitt Lymphoma , Epstein-Barr Virus Infections , Valproic Acid/analogs & derivatives , Humans , Burkitt Lymphoma/drug therapy , Burkitt Lymphoma/genetics , Herpesvirus 4, Human/physiology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/metabolism , Epstein-Barr Virus Infections/drug therapy , Virus Activation , Gene Expression Profiling , Butyrates/pharmacology
20.
Retrovirology ; 21(1): 6, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38580979

ABSTRACT

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.


Subject(s)
HIV Infections , HIV-1 , Humans , HIV-1/physiology , Virus Latency , Positive Transcriptional Elongation Factor B/genetics , Positive Transcriptional Elongation Factor B/metabolism , CD4-Positive T-Lymphocytes , Proviruses/metabolism , Virus Activation
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