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World Journal of Gastroenterology Feb 2024Approximately 12-72 million people worldwide are co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). This concurrent infection can lead to several...
Approximately 12-72 million people worldwide are co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). This concurrent infection can lead to several severe outcomes with hepatic disease, such as cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, being the most common. Over the past few decades, a correlation between viral hepatitis and autoimmune diseases has been reported. Furthermore, autoantibodies have been detected in the serum of patients co-infected with HBV/HDV, and autoimmune features have been reported. However, to date, very few cases of clinically significant autoimmune hepatitis (AIH) have been reported in patients with HDV infection, mainly in those who have received treatment with pegylated interferon. Interestingly, there are some patients with HBV infection and AIH in whom HDV infection is unearthed after receiving treatment with immunosuppressants. Consequently, several questions remain unanswered with the challenge to distinguish whether it is autoimmune or "autoimmune-like" hepatitis being the most crucial. Second, it remains uncertain whether autoimmunity is induced by HBV or delta virus. Finally, we investigated whether the cause of AIH lies in the previous treatment of HDV with pegylated interferon. These pressing issues should be elucidated to clarify whether new antiviral treatments for HDV, such as Bulevirtide or immu-nosuppressive drugs, are more appropriate for the management of patients with HDV and AIH.
Topics: Humans; Hepatitis Delta Virus; Hepatitis, Autoimmune; Hepatitis B; Hepatitis B virus; Interferons; Liver Neoplasms; Polyethylene Glycols; Antiviral Agents
PubMed: 38516234
DOI: 10.3748/wjg.v30.i8.799 -
Multiple Sclerosis (Houndmills,... Apr 2024Epstein-Barr virus (EBV) is thought to be a necessary causative agent in the development of multiple sclerosis (MS). Infectious mononucleosis (IM), which occurs up to...
BACKGROUND
Epstein-Barr virus (EBV) is thought to be a necessary causative agent in the development of multiple sclerosis (MS). Infectious mononucleosis (IM), which occurs up to 70% of adolescents and young adults with primary EBV infection, appears to be a further risk factor but few studies have been highly powered enough to explore this association by time since IM diagnosis.
OBJECTIVE
The objective was to quantify the risk of MS in individuals with IM compared with the general population, with particular focus on time since IM diagnosis.
METHODS
In this retrospective cohort study using English national Hospital Episode Statistics from 2003 to 2023, patients with a hospital diagnosis of IM were compared with the general population for MS incidence.
RESULTS
MS incidence in patients with IM was nearly three times higher than the general population after multivariable adjustment (adjusted hazard ratio = 2.8, 95% confidence interval (CI = 2.3-3.4), driven by strong associations at long time intervals (>5 years) between IM diagnosis and subsequent MS diagnosis.
CONCLUSION
While EBV infection may be a prerequisite for MS, the disease process of IM (i.e. the body's defective immune response to primary EBV infection) seems to be, in addition, implicated over the long term.
Topics: Adolescent; Young Adult; Humans; Infectious Mononucleosis; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Retrospective Studies; Cohort Studies; Multiple Sclerosis; Hospital Records; England; Hospitals
PubMed: 38511730
DOI: 10.1177/13524585241237707 -
Cellular and Molecular Life Sciences :... Mar 2024Propagation of viruses requires interaction with host factors in infected cells and repression of innate immune responses triggered by the host viral sensors. Cytosolic...
Propagation of viruses requires interaction with host factors in infected cells and repression of innate immune responses triggered by the host viral sensors. Cytosolic DNA sensing pathway of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) is a major component of the antiviral response to DNA viruses, also known to play a relevant role in response to infection by RNA viruses, including foot-and-mouth disease virus (FMDV). Here, we provide supporting evidence of cGAS degradation in swine cells during FMDV infection and show that the two virally encoded proteases, Leader (Lpro) and 3Cpro, target cGAS for cleavage to dampen the cGAS/STING-dependent antiviral response. The specific target sequence sites on swine cGAS were identified as Q140/T141 for the FMDV 3Cpro and the KVKNNLKRQ motif at residues 322-330 for Lpro. Treatment of swine cells with inhibitors of the cGAS/STING pathway or depletion of cGAS promoted viral infection, while overexpression of a mutant cGAS defective for cGAMP synthesis, unlike wild type cGAS, failed to reduce FMDV replication. Our findings reveal a new mechanism of RNA viral antagonism of the cGAS-STING innate immune sensing pathway, based on the redundant degradation of cGAS through the concomitant proteolytic activities of two proteases encoded by an RNA virus, further proving the key role of cGAS in restricting FMDV infection.
Topics: Animals; Swine; Foot-and-Mouth Disease Virus; Peptide Hydrolases; Signal Transduction; Immunity, Innate; Endopeptidases; Nucleotidyltransferases; Antiviral Agents
PubMed: 38509419
DOI: 10.1007/s00018-024-05190-7 -
Nature Communications Mar 2024Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na-taurocholate...
Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor's extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.
Topics: Humans; Hepatitis B virus; Antiviral Agents; Hepatitis B; Receptors, Virus; Bile Acids and Salts; Hepatitis Delta Virus; Symporters; Virus Internalization; Hepatocytes; Lipopeptides
PubMed: 38509088
DOI: 10.1038/s41467-024-46706-w -
The Journal of Biological Chemistry Apr 2024Interferon (IFN) regulatory factors (IRF) are key transcription factors in cellular antiviral responses. IRF7, a virus-inducible IRF, expressed primarily in myeloid...
Interferon (IFN) regulatory factors (IRF) are key transcription factors in cellular antiviral responses. IRF7, a virus-inducible IRF, expressed primarily in myeloid cells, is required for transcriptional induction of interferon α and antiviral genes. IRF7 is activated by virus-induced phosphorylation in the cytoplasm, leading to its translocation to the nucleus for transcriptional activity. Here, we revealed a nontranscriptional activity of IRF7 contributing to its antiviral functions. IRF7 interacted with the pro-inflammatory transcription factor NF-κB-p65 and inhibited the induction of inflammatory target genes. Using knockdown, knockout, and overexpression strategies, we demonstrated that IRF7 inhibited NF-κB-dependent inflammatory target genes, induced by virus infection or toll-like receptor stimulation. A mutant IRF7, defective in transcriptional activity, interacted with NF-κB-p65 and suppressed NF-κB-induced gene expression. A single-action IRF7 mutant, active in anti-inflammatory function, but defective in transcriptional activity, efficiently suppressed Sendai virus and murine hepatitis virus replication. We, therefore, uncovered an anti-inflammatory function for IRF7, independent of transcriptional activity, contributing to the antiviral response of IRF7.
Topics: Animals; Humans; Mice; HEK293 Cells; Inflammation; Interferon Regulatory Factor-7; NF-kappa B; Sendai virus; Transcription Factor RelA; Virus Replication; Mutation; Gene Expression Regulation; Murine hepatitis virus; Coronavirus Infections; Respirovirus Infections
PubMed: 38508315
DOI: 10.1016/j.jbc.2024.107200 -
Current Opinion in HIV and AIDS May 2024Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and reignite viral replication if therapy is interrupted. Persistence of the viral reservoir... (Review)
Review
PURPOSE OF REVIEW
Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and reignite viral replication if therapy is interrupted. Persistence of the viral reservoir in people with HIV-1 (PWH) is the main obstacle to an HIV-1 cure. The reservoirs are not transcriptionally silent, and viral transcripts can be detected in most ART-treated individuals. Here, we review the recent progress in the characterization of persistent HIV-1 transcription during ART.
RECENT FINDINGS
Evidence from several studies indicates that, although cell-associated unspliced (US) HIV-1 RNA is abundantly expressed in ART-treated PWH, intact full-length US transcripts are rare and most US RNA is derived from defective proviruses. The transcription- and translation-competent defective proviruses, previously considered irrelevant, are increasingly being linked to residual HIV-1 pathogenesis under suppressive ART. Recent data suggest a continuous crosstalk between the residual HIV-1 activity under ART and the immune system. Persistent HIV-1 transcription on ART, despite being mostly derived from defective proviruses, predicts viral rebound upon therapy interruption, suggesting its role as an indicator of the strength of the host antiviral immune response that is shaping the viral rebound.
SUMMARY
In light of the recent findings, the significance of persistent HIV-1 transcription during ART for the long-term health of PWH and the cure research should be reassessed.
Topics: Humans; HIV Infections; HIV-1; Anti-Retroviral Agents; Virus Replication; Proviruses; RNA, Viral; CD4-Positive T-Lymphocytes; Viral Load
PubMed: 38502547
DOI: 10.1097/COH.0000000000000849 -
Journal of Immunology (Baltimore, Md. :... May 2024Increased receptor binding affinity may allow viruses to escape from Ab-mediated inhibition. However, how high-affinity receptor binding affects innate immune escape and...
Increased receptor binding affinity may allow viruses to escape from Ab-mediated inhibition. However, how high-affinity receptor binding affects innate immune escape and T cell function is poorly understood. In this study, we used the lymphocytic choriomeningitis virus (LCMV) murine infection model system to create a mutated LCMV exhibiting higher affinity for the entry receptor α-dystroglycan (LCMV-GPH155Y). We show that high-affinity receptor binding results in increased viral entry, which is associated with type I IFN (IFN-I) resistance, whereas initial innate immune activation was not impaired during high-affinity virus infection in mice. Consequently, IFN-I resistance led to defective antiviral T cell immunity, reduced type II IFN, and prolonged viral replication in this murine model system. Taken together, we show that high-affinity receptor binding of viruses can trigger innate affinity escape including resistance to IFN-I resulting in prolonged viral replication.
Topics: Mice; Animals; Virus Internalization; Mice, Knockout; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Virus Replication; Mice, Inbred C57BL; Immunity, Innate
PubMed: 38497668
DOI: 10.4049/jimmunol.2300637 -
Frontiers in Immunology 2024Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit...
Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit viral replication. Activation of type I interferon is regulated by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation by the upstream kinase, TBK1, during viral infection. However, the mechanisms by which TBK1 achieves activation to support signaling to IRF3 remain incompletely understood. Here we identified the E3 ubiquitin ligase, tripartite motif containing 28 (TRIM28), as a positive regulator of type I interferon activation by facilitating TBK1 signaling. Genetic deletion of TRIM28 via CRISPR-Cas9 editing resulted in impaired type I interferon activation upon both RNA and DNA virus challenge, corresponding with increased susceptibility to virus infections in TRIM28 knockout cells. Mechanistically, TRIM28 interacted with TBK1 and mediated the assembly of K63-linked ubiquitin chains onto TBK1, a post-translational modification shown to augment TBK1 signal transmission events. TRIM28 knockout cells further displayed defective TBK1 phosphorylation and complex assembly with IRF3, resulting in impaired IRF3 phosphorylation. Altogether, our data demonstrate TBK1 to be a novel substrate for TRIM28 and identify TRIM28 as an essential regulatory factor in controlling innate antiviral immune responses.
Topics: Protein Serine-Threonine Kinases; Interferon Type I; Signal Transduction; Phosphorylation; Interferon-beta
PubMed: 38495890
DOI: 10.3389/fimmu.2024.1279920 -
Journal of Clinical Immunology Mar 2024Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. To provide understanding on inflammatory myocarditis, we describe...
Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. To provide understanding on inflammatory myocarditis, we describe clinical, genetic, and immunological properties of a young male patient who suffered from recurrent myocarditis episodes since the age of four years. Electrocardiography, troponin I/T, echocardiography, myocardial magnetic resonance imaging and histological findings were consistent with recurrent myocarditis episodes. Homozygous c.245 A > G p.Tyr82Cys pathogenic variant in Hepatitis A Virus Cellular Receptor 2 (HAVCR2) gene encoding T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) receptor was found. Peripheral blood mononuclear cells were collected when the patient was asymptomatic; CD4 and CD8 T lymphoblasts, CD56 natural killer cells and CD14 monocytes were negative for surface TIM-3 expression. In vitro, TLR4 mediated interleukin-1β (IL-1β) response was high after LPS/ATP stimulation. Clinical symptoms responded to IL-1 receptor antagonist anakinra. TIM-3 p.Tyr82Cys CD4 and CD8 T cell proliferation in vitro was unrestrained. Findings on IL-2, interferon gamma, regulatory T cells, signal transducer and activator of transcription (STAT) 1, 3 and 4 phosphorylation, and PD-1 and LAG-3 checkpoint inhibitor receptor analyses were comparable to controls. We conclude that TIM-3 deficiency due to homozygous HAVCR2 c.245 A > G p.Tyr82Cys pathogenic variant in the patient described here is associated with autoinflammatory symptoms limited to early onset recurrent febrile myocarditis. Excessive IL-1β production and defective regulation of T cell proliferation may contribute to this clinical condition responsive to anakinra treatment.
Topics: Humans; Male; Child, Preschool; Hepatitis A Virus Cellular Receptor 2; Myocarditis; Leukocytes, Mononuclear; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Germ Cells
PubMed: 38485795
DOI: 10.1007/s10875-024-01685-x -
Plant Molecular Biology Mar 2024In plants, cytidine-to-uridine (C-to-U) editing is a crucial step in processing mitochondria- and chloroplast-encoded transcripts. This editing requires nuclear-encoded...
In plants, cytidine-to-uridine (C-to-U) editing is a crucial step in processing mitochondria- and chloroplast-encoded transcripts. This editing requires nuclear-encoded proteins including members of the pentatricopeptide (PPR) family, especially PLS-type proteins carrying the DYW domain. IPI1/emb175/PPR103 is a nuclear gene encoding a PLS-type PPR protein essential for survival in Arabidopsis thaliana and maize. Arabidopsis IPI1 was identified as likely interacting with ISE2, a chloroplast-localized RNA helicase associated with C-to-U RNA editing in Arabidopsis and maize. Notably, while the Arabidopsis and Nicotiana IPI1 orthologs possess complete DYW motifs at their C-termini, the maize homolog, ZmPPR103, lacks this triplet of residues which are essential for editing. In this study we examined the function of IPI1 in chloroplast RNA processing in N. benthamiana to gain insight into the importance of the DYW domain to the function of the EMB175/PPR103/ IPI1 proteins. Structural predictions suggest that evolutionary loss of residues identified as critical for catalyzing C-to-U editing in other members of this class of proteins, were likely to lead to reduced or absent editing activity in the Nicotiana and Arabidopsis IPI1 orthologs. Virus-induced gene silencing of NbIPI1 led to defects in chloroplast ribosomal RNA processing and changes to stability of rpl16 transcripts, revealing conserved function with its maize ortholog. NbIPI1-silenced plants also had defective C-to-U RNA editing in several chloroplast transcripts, a contrast from the finding that maize PPR103 had no role in editing. The results indicate that in addition to its role in transcript stability, NbIPI1 may contribute to C-to-U editing in N. benthamiana chloroplasts.
Topics: Arabidopsis; RNA, Chloroplast; Arabidopsis Proteins; Zea mays; RNA; Chloroplasts
PubMed: 38485794
DOI: 10.1007/s11103-024-01424-1