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EMBO Reports Sep 2023Interferons control viral infection by inducing the expression of antiviral effector proteins encoded by interferon-stimulated genes (ISGs). The field has mostly focused...
Interferons control viral infection by inducing the expression of antiviral effector proteins encoded by interferon-stimulated genes (ISGs). The field has mostly focused on identifying individual antiviral ISG effectors and defining their mechanisms of action. However, fundamental gaps in knowledge about the interferon response remain. For example, it is not known how many ISGs are required to protect cells from a particular virus, though it is theorized that numerous ISGs act in concert to achieve viral inhibition. Here, we used CRISPR-based loss-of-function screens to identify a markedly limited set of ISGs that confer interferon-mediated suppression of a model alphavirus, Venezuelan equine encephalitis virus (VEEV). We show via combinatorial gene targeting that three antiviral effectors-ZAP, IFIT3, and IFIT1-together constitute the majority of interferon-mediated restriction of VEEV, while accounting for < 0.5% of the interferon-induced transcriptome. Together, our data suggest a refined model of the antiviral interferon response in which a small subset of "dominant" ISGs may confer the bulk of the inhibition of a given virus.
Topics: Animals; Horses; Interferons; Cell Line; Virus Replication; Antiviral Agents; Encephalitis Virus, Venezuelan Equine; Viruses
PubMed: 37497756
DOI: 10.15252/embr.202356901 -
Expert Opinion on Emerging Drugs Dec 2023Chronic hepatitis delta (CHD) is the most severe form of chronic viral hepatitis. Until recently, its treatment consisted of pegylated interferon alfa (pegIFN) use.
INTRODUCTION
Chronic hepatitis delta (CHD) is the most severe form of chronic viral hepatitis. Until recently, its treatment consisted of pegylated interferon alfa (pegIFN) use.
AREAS COVERED
Current and new drugs for treating CHD. Virus entry inhibitor bulevirtide has received conditional approval by the European Medicines Agency. Prenylation inhibitor lonafarnib and pegIFN lambda are in phase 3 and nucleic acid polymers in phase 2 of drug development.
EXPERT OPINION
Bulevirtide appears to be safe. Its antiviral efficacy increases with treatment duration. Combining bulevirtide with pegIFN has the highest antiviral efficacy short-term. The prenylation inhibitor lonafarnib prevents hepatitis D virus assembly. It is associated with dose-dependent gastrointestinal toxicity and is better used with ritonavir which increases liver lonafarnib concentrations. Lonafarnib also possesses immune modulatory properties which explains some post-treatment beneficial flare cases. Combining lonafarnib/ritonavir with pegIFN has superior antiviral efficacy. Nucleic acid polymers are amphipathic oligonucleotides whose effect appears to be a consequence of phosphorothioate modification of internucleotide linkages. These compounds led to HBsAg clearance in a sizable proportion of patients. PegIFN lambda is associated with less IFN typical side effects. In a phase 2 study it led to 6 months off treatment viral response in one third of patients.
Topics: Humans; Antiviral Agents; Hepatitis D; Hepatitis D, Chronic; Nucleic Acids; Polyethylene Glycols; Polymers; Ritonavir; Treatment Outcome
PubMed: 37096555
DOI: 10.1080/14728214.2023.2205639 -
International Journal of Molecular... Aug 2023Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for... (Review)
Review
Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for its translation into proteins. Along with transcription and translation, mRNA export through the nuclear pore complex (NPC) is an essential regulatory step in eukaryotic gene expression. Multiple factors regulate mRNA export and hence gene expression. Interestingly, proteins from certain types of viruses interact with these factors in infected cells, and such an interaction interferes with the mRNA export of the host cell in favor of viral RNA export. Thus, these viruses hijack the host mRNA nuclear export mechanism, leading to a reduction in host gene expression and the downregulation of immune/antiviral responses. On the other hand, the viral mRNAs successfully evade the host surveillance system and are efficiently exported from the nucleus to the cytoplasm for translation, which enables the continuation of the virus life cycle. Here, we present this review to summarize the mechanisms by which viruses suppress host mRNA nuclear export during infection, as well as the key strategies that viruses use to facilitate their mRNA nuclear export. These studies have revealed new potential antivirals that may be used to inhibit viral mRNA transport and enhance host mRNA nuclear export, thereby promoting host gene expression and immune responses.
Topics: Humans; Active Transport, Cell Nucleus; Virus Diseases; Antiviral Agents; RNA Transport; Eukaryota; RNA, Messenger
PubMed: 37628773
DOI: 10.3390/ijms241612593 -
Nature Reviews. Microbiology May 2024Autophagy is a constitutive cellular process of degradation required to maintain homeostasis and turn over spent organelles and aggregated proteins. For some viruses,... (Review)
Review
Autophagy is a constitutive cellular process of degradation required to maintain homeostasis and turn over spent organelles and aggregated proteins. For some viruses, the process can be antiviral, degrading viral proteins or virions themselves. For many other viruses, the induction of the autophagic process provides a benefit and promotes viral replication. In this Review, we survey the roles that the autophagic pathway plays in the replication of viruses. Most viruses that benefit from autophagic induction block autophagic degradation, which is a 'bend, but don't break' strategy initiating but limiting a potentially antiviral response. In almost all cases, it is other effects of the redirected autophagic machinery that benefit these viruses. This rapid mechanism to generate small double-membraned vesicles can be usurped to shape membranes for viral genome replication and virion maturation. However, data suggest that autophagic maintenance of cellular homeostasis is crucial for the initiation of infection, as viruses have evolved to replicate in normal, healthy cells. Inhibition of autophagic degradation is important once infection has initiated. Although true degradative autophagy is probably a negative for most viruses, initiating nondegradative autophagic membranes benefits a wide variety of viruses.
Topics: Viruses; Viral Proteins; Virion; Autophagy; Antiviral Agents; Virus Replication
PubMed: 38102460
DOI: 10.1038/s41579-023-00995-y -
Nature Reviews. Microbiology Jul 2024The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused substantial morbidity and mortality,... (Review)
Review
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused substantial morbidity and mortality, and serious social and economic disruptions worldwide. Unvaccinated or incompletely vaccinated older individuals with underlying diseases are especially prone to severe disease. In patients with non-fatal disease, long COVID affecting multiple body systems may persist for months. Unlike SARS-CoV and Middle East respiratory syndrome coronavirus, which have either been mitigated or remained geographically restricted, SARS-CoV-2 has disseminated globally and is likely to continue circulating in humans with possible emergence of new variants that may render vaccines less effective. Thus, safe, effective and readily available COVID-19 therapeutics are urgently needed. In this Review, we summarize the major drug discovery approaches, preclinical antiviral evaluation models, representative virus-targeting and host-targeting therapeutic options, and key therapeutics currently in clinical use for COVID-19. Preparedness against future coronavirus pandemics relies not only on effective vaccines but also on broad-spectrum antivirals targeting conserved viral components or universal host targets, and new therapeutics that can precisely modulate the immune response during infection.
Topics: Humans; Antiviral Agents; COVID-19 Drug Treatment; Drug Discovery; SARS-CoV-2; COVID-19; Animals
PubMed: 38622352
DOI: 10.1038/s41579-024-01036-y -
Viruses Sep 2023Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of... (Review)
Review
Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of early antiviral type I IFN response against virus invasion has been emphasized during COVID-19 as well as in studies on the microbiome. Further, type I IFNs can directly act on various immune cells to enhance protective host immune responses to viral infections. However, accumulating data indicate that IFN responses can be harmful to the host by instigating inflammatory responses or inducing T cell suppression during virus infections. Also, inhibition of lymphocyte and dendritic cell development can be caused by type I IFN, which is independent of the traditional signal transducer and activator of transcription 1 signaling. Additionally, IFNs were shown to impair airway epithelial cell proliferation, which may affect late-stage lung tissue recovery from the infection. As such, type I IFN-virus interaction research is diverse, including host antiviral innate immune mechanisms in cells, viral strategies of IFN evasion, protective immunity, excessive inflammation, immune suppression, and regulation of tissue repair. In this report, these IFN activities are summarized with an emphasis placed on the functions of type I IFNs recently observed during acute or chronic virus infections.
Topics: Humans; Interferon Type I; COVID-19; Virus Diseases; Antiviral Agents; Virus Replication
PubMed: 37766322
DOI: 10.3390/v15091916 -
The Journal of Infectious Diseases Feb 2024This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56%... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).
METHODS
Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.
RESULTS
At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n = 1) and UL97 F342Y (n = 3). Posttreatment, emergent maribavir resistance mutations were detected in 60 (26%) of those randomized to maribavir, including 49 (48%) of 103 nonresponders and 25 (86%) of the 29 nonresponders where viral DNA initially cleared then rebounded while on maribavir. The most common maribavir resistance mutations were UL97 T409M (n = 34), H411Y (n = 26), and C480F (n = 21), first detected 26 to 130 (median 56) days after starting maribavir.
CONCLUSIONS
Baseline maribavir resistance was rare. Drug resistance to standard cytomegalovirus antivirals did not preclude treatment response to maribavir. Rebound in plasma cytomegalovirus DNA while on maribavir strongly suggests emerging drug resistance.
CLINICAL TRIALS REGISTRATION
NCT02931539.
Topics: Humans; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; DNA; Drug Resistance, Viral; Ganciclovir; Mutation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Transplant Recipients
PubMed: 37506264
DOI: 10.1093/infdis/jiad293 -
Nature Communications Dec 2023Autophagy receptor NDP52 triggers bacterial autophagy against infection. However, the ability of NDP52 to protect against viral infection has not been established. We...
Autophagy receptor NDP52 triggers bacterial autophagy against infection. However, the ability of NDP52 to protect against viral infection has not been established. We show that NDP52 binds to envelope proteins of hepatitis B virus (HBV) and triggers a degradation process that promotes HBV clearance. Inactivating NDP52 in hepatocytes results in decreased targeting of viral envelopes in the lysosome and increased levels of viral replication. NDP52 inhibits HBV at both viral entry and late replication stages. In contrast to NDP52-mediated bacterial autophagy, lysosomal degradation of HBV envelopes is independent of galectin 8 and ATG5. NDP52 forms complex with Rab9 and viral envelope proteins and links HBV to Rab9-dependent lysosomal degradation pathway. These findings reveal that NDP52 acts as a sensor for HBV infection, which mediates a unique antiviral response to eliminate the virus. This work also suggests direct roles for autophagy receptors in other lysosomal degradation pathways than canonical autophagy.
Topics: Humans; Hepatitis B virus; Hepatitis B; Hepatocytes; Autophagy; Lysosomes; Antiviral Agents; Virus Replication
PubMed: 38114531
DOI: 10.1038/s41467-023-44201-2 -
Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.Journal of Hepatology Feb 2024Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with...
BACKGROUND & AIMS
Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system.
METHODS
To leverage this opportunity, we used plate-based single-cell RNA-seq to deeply profile myeloid cells from liver fine needle aspirates in patients with HCV before and after DAA treatment. We comprehensively characterised liver neutrophils, eosinophils, mast cells, conventional dendritic cells, plasmacytoid dendritic cells, classical monocytes, non-classical monocytes, and macrophages, and defined fine-grained subpopulations of several cell types.
RESULTS
We discovered cell type-specific changes post-cure, including an increase in MCM7+STMN1+ proliferating CD1C+ conventional dendritic cells, which may support restoration from chronic exhaustion. We observed an expected downregulation of interferon-stimulated genes (ISGs) post-cure as well as an unexpected inverse relationship between pre-treatment viral load and post-cure ISG expression in each cell type, revealing a link between viral loads and sustained modifications of the host's immune system. We found an upregulation of PD-L1/L2 gene expression in ISG-high neutrophils and IDO1 expression in eosinophils, pinpointing cell subpopulations crucial for immune regulation. We identified three recurring gene programmes shared by multiple cell types, distilling core functions of the myeloid compartment.
CONCLUSIONS
This comprehensive single-cell RNA-seq atlas of human liver myeloid cells in response to cure of chronic viral infections reveals principles of liver immunity and provides immunotherapeutic insights.
CLINICAL TRIAL REGISTRATION
This study is registered at ClinicalTrials.gov (NCT02476617).
IMPACT AND IMPLICATIONS
Chronic viral liver infections continue to be a major public health problem. Single-cell characterisation of liver immune cells during hepatitis C and post-cure provides unique insights into the architecture of liver immunity contributing to the resolution of the first curable chronic viral infection of humans. Multiple layers of innate immune regulation during chronic infections and persistent immune modifications after cure are revealed. Researchers and clinicians may leverage these findings to develop methods to optimise the post-cure environment for HCV and develop novel therapeutic approaches for other chronic viral infections.
Topics: Humans; Antiviral Agents; Persistent Infection; Hepatitis C, Chronic; Hepatitis C; Hepacivirus
PubMed: 36972796
DOI: 10.1016/j.jhep.2023.02.040 -
Cellular & Molecular Immunology Dec 2023The G protein-coupled receptor ADGRE5 (CD97) binds to various metabolites that play crucial regulatory roles in metabolism. However, its function in the antiviral innate...
The G protein-coupled receptor ADGRE5 (CD97) binds to various metabolites that play crucial regulatory roles in metabolism. However, its function in the antiviral innate immune response remains to be determined. In this study, we report that CD97 inhibits virus-induced type-I interferon (IFN-I) release and enhances RNA virus replication in cells and mice. CD97 was identified as a new negative regulator of the innate immune receptor RIG-I, and RIG-1 degradation led to the suppression of the IFN-I signaling pathway. Furthermore, overexpression of CD97 promoted the ubiquitination of RIG-I, resulting in its degradation, but did not impact its mRNA expression. Mechanistically, CD97 upregulates RNF125 expression to induce RNF125-mediated RIG-I degradation via K48-linked ubiquitination at Lys181 after RNA virus infection. Most importantly, CD97-deficient mice are more resistant than wild-type mice to RNA virus infection. We also found that sanguinarine-mediated inhibition of CD97 effectively blocks VSV and SARS-CoV-2 replication. These findings elucidate a previously unknown mechanism through which CD97 negatively regulates RIG-I in the antiviral innate immune response and provide a molecular basis for the development of new therapeutic strategies and the design of targeted antiviral agents.
Topics: Animals; Mice; Antiviral Agents; DEAD Box Protein 58; Immunity, Innate; Receptors, G-Protein-Coupled; RNA Virus Infections; RNA Viruses; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 37978243
DOI: 10.1038/s41423-023-01103-z