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International Journal of Infectious... Dec 2023After the third year of the COVID-19 pandemic, most of the severe COVID-19 burden falls upon immunocompromised patients who cannot mount an endogenous immune response... (Review)
Review
OBJECTIVES
After the third year of the COVID-19 pandemic, most of the severe COVID-19 burden falls upon immunocompromised patients who cannot mount an endogenous immune response after both vaccination and/or natural infection. They also experience persistent SARS-CoV-2 infection with high viral loads often unsuccessfully managed by the standard antiviral monotherapy regimen initially validated for treatment of COVID-19 immunocompetent patients, only. The off-label prescription of such monotherapy regimens in immunocompromised patients is likely to drive the emergence of treatment-related immune escape, relapses, excess morbidity, and mortality from both COVID-19 and delayed treatment of the underlying disorders. A possible treatment approach to mitigate such consequence is based on combined antiviral therapies.
METHODS
We searched PubMed for case reports, case series and clinical trials reporting the usage of combined antiviral therapies for COVID-19.
RESULTS
In this narrative review, we show that combinations of either small molecule antivirals or small molecule antiviral plus passive immunotherapies are safe and effective in small cohorts reported so far.
CONCLUSION
Considering the progressive loss of efficacy of all authorized anti-spike monoclonal antibodies, promising regimen options are reserved to combinations of small molecule antivirals and COVID-19 convalescent plasma from vaccinated donors.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; COVID-19 Serotherapy; Antiviral Agents; Immunocompromised Host
PubMed: 37778409
DOI: 10.1016/j.ijid.2023.09.021 -
International Journal of Antimicrobial... Sep 2023This study aimed to evaluate the antiviral effects and safety of nafamostat in early-onset patients with coronavirus disease 2019 (COVID-19). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This study aimed to evaluate the antiviral effects and safety of nafamostat in early-onset patients with coronavirus disease 2019 (COVID-19).
METHODS
In this exploratory multicentre randomized controlled trial, patients were assigned to three groups within 5 days of symptom onset, with 10 participants in each group: nafamostat at either 0.2 mg/kg/h or 0.1 mg/kg/h or a standard-of-care group. The primary endpoint was area under the curve for decrease in SARS-CoV-2 viral load in nasopharyngeal samples from baseline to day 6.
RESULTS
Of the 30 randomized patients, 19 received nafamostat. Overall, 10 patients received low-dose nafamostat, 9 patients received high-dose nafamostat, and 10 received standard-of-care. The detected viruses were Omicron strains. The regression coefficient for area under the curve for decrease in viral load as the response variable and nafamostat dose per body weight as the explanatory variable showed a significant relationship of -40.1 (95% confidence interval, -74.1 to -6.2; P = 0.022). Serious adverse events were not observed in either group. Phlebitis occurred in ca. 50% of patients treated with nafamostat.
CONCLUSIONS
Nafamostat exerts virus load-reducing effects in patients with early-onset COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Antiviral Agents; Guanidines; Treatment Outcome
PubMed: 37429450
DOI: 10.1016/j.ijantimicag.2023.106922 -
Aging Cell Oct 2023Biological aging in people with HIV (PWH) with prolonged successful antiretroviral therapy (ART) is convoluted and poorly defined. Here, we aimed to investigate the...
Biological aging in people with HIV (PWH) with prolonged successful antiretroviral therapy (ART) is convoluted and poorly defined. Here, we aimed to investigate the transcriptomics age estimator (TAE) in a cohort of 178 PWH on prolonged successful ART with immune reconstitution and viral suppression from the Copenhagen Comorbidity (COCOMO) cohort. We also used 143 clinical, demographical, and lifestyle factors to identify the confounders potentially responsible or associated with age acceleration. Among the PWH, 43% had an accelerated aging process (AAP), and 21% had decelerated aging process (DAP). DAP is linked with older age, European ancestry, and higher use of tenofovir disoproxil/alafenamide fumarate. A directionally class-based gene set enrichment analysis identified the upregulation of inflammatory pathways (e.g., cytokine and Retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathways) and immune response like T-cell receptor signaling, antigen processing, and presentation in AAP and the downregulation of metabolic processes like oxidative phosphorylation, pyruvate metabolism.
Topics: Humans; HIV Infections; Anti-HIV Agents; Emtricitabine; Transcriptome; HIV-1; Tenofovir; Adenine
PubMed: 37548368
DOI: 10.1111/acel.13951 -
Viruses Jan 2024The type-I interferon (IFN) response constitutes the major innate immune pathway against viruses in mammals. Despite its critical importance for antiviral defence, this... (Meta-Analysis)
Meta-Analysis Review
The type-I interferon (IFN) response constitutes the major innate immune pathway against viruses in mammals. Despite its critical importance for antiviral defence, this pathway is inactive during early embryonic development. There seems to be an incompatibility between the IFN response and pluripotency, the ability of embryonic cells to develop into any cell type of an adult organism. Instead, pluripotent cells employ alternative ways to defend against viruses that are typically associated with safeguard mechanisms against transposable elements. The absence of an inducible IFN response in pluripotent cells and the constitutive activation of the alternative antiviral pathways have led to the hypothesis that embryonic cells are highly resistant to viruses. However, some findings challenge this interpretation. We have performed a meta-analysis that suggests that the susceptibility of pluripotent cells to viruses is directly correlated with the presence of receptors or co-receptors for viral adhesion and entry. These results challenge the current view of pluripotent cells as intrinsically resistant to infections and raise the fundamental question of why these cells have sacrificed the major antiviral defence pathway if this renders them susceptible to viruses.
Topics: Animals; Interferon Type I; Viruses; Mammals; Antiviral Agents; Immunity, Innate
PubMed: 38399949
DOI: 10.3390/v16020173 -
Virus Research Sep 2023Schlafen (SLFN) proteins are a subset of interferon-stimulated early response genes with antiviral properties. An antiviral mechanism of SLFN11 was previously...
Schlafen (SLFN) proteins are a subset of interferon-stimulated early response genes with antiviral properties. An antiviral mechanism of SLFN11 was previously demonstrated in human immunodeficiency virus type 1 (HIV-1)-infected cells, and it was shown that SLFN11 inhibited HIV-1 virus production in a codon usage-specific manner. The codon usage patterns of many viruses are vastly different from those of their hosts. The codon usage-specific inhibition of HIV-1 expression by SLFN11 suggests that SLFN11 may be able to inhibit other viruses with a suboptimal codon usage pattern. However, the effect of SLFN11 on the replication of influenza A virus (IAV) has never been reported. The induction of SLFN11 expression was observed upon IAV infection. The reduction of SLFN11 expression also promotes influenza virus replication. Moreover, we found that overexpression of SLFN11 could reduce the expression of a reporter gene with a viral codon usage pattern, and the inhibition of viral hemagglutinin (HA) gene was codon-specific as the expression of codon optimized HA was not affected. These results indicate that SLFN11 inhibits the influenza A virus in a codon-specific manner and that SLFN11 may contribute to innate defense against influenza A viruses.
Topics: Humans; Influenza A virus; Proteins; Interferons; Virus Replication; Codon; Antiviral Agents; Influenza, Human; Nuclear Proteins
PubMed: 37356582
DOI: 10.1016/j.virusres.2023.199162 -
Nature Communications Mar 2024Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered...
Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
Topics: Animals; Mice; Mannose-6-Phosphate Isomerase; Glycosylation; Mannose; Glucose; Antiviral Agents
PubMed: 38459021
DOI: 10.1038/s41467-024-46415-4 -
MBio Aug 2023The host innate immune system's defense against viral infections depends heavily on type I interferon (IFN-I) production. Research into the mechanisms of virus-host...
The host innate immune system's defense against viral infections depends heavily on type I interferon (IFN-I) production. Research into the mechanisms of virus-host interactions is essential for developing novel antiviral therapies. In this study, we compared the effect of the five members of the microRNA-200 (miR-200) family on IFN-I production during viral infection and found that miR-200b-3p displayed the most pronounced regulatory effect. During viral infection, we discovered that the transcriptional level of microRNA-200b-3p (miR-200b-3p) increased with the infection of influenza virus (IAV) and vesicular stomatitis virus (VSV), and miR-200b-3p production was modulated by the activation of the ERK and p38 pathways. We identified cAMP response element binding protein (CREB) as a novel transcription factor that binds to the miR-200b-3p promoter. MiR-200b-3p reduces NF-κB and IRF3-mediated IFN-I production by targeting the 3' untranslated region (3' UTR) of TBK1 mRNA. Applying miR-200b-3p inhibitor enhances IFN-I production in IAV and VSV-infected mouse models, thus inhibiting viral replication and improving mouse survival ratio. Importantly, in addition to IAV and VSV, miR-200b-3p inhibitors exhibited potent antiviral effects against multiple pathogenic viruses threatening human health worldwide. Overall, our study suggests that miR-200b-3p might be a potential therapeutic target for broad-spectrum antiviral therapy. IMPORTANCE The innate immune response mediated by type I interferon (IFN-I) is essential for controlling viral replication. MicroRNAs (miRNAs) have been found to regulate the IFN signaling pathway. In this study, we describe a novel function of miRNA-200b-3p in negatively regulating IFN-I production during viral infection. miRNA-200b-3p was upregulated by the MAPK pathway activated by IAV and VSV infection. The binding of miRNA-200b-3p to the 3' UTR of TBK1 mRNA reduced IFN-I activation mediated by IRF3 and NF-κB. Application of miR-200b-3p inhibitors exhibited potent antiviral effects against multiple RNA and DNA viruses. These results provide fresh insight into understanding the impact of miRNAs on host-virus interactions and reveal a potential therapeutic target for common antiviral intervention.
Topics: Humans; Animals; Mice; NF-kappa B; 3' Untranslated Regions; MicroRNAs; Virus Diseases; Interferon Type I; Antiviral Agents; Virus Replication; Protein Serine-Threonine Kinases
PubMed: 37222520
DOI: 10.1128/mbio.00867-23 -
Viruses Jan 2024Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent... (Review)
Review
Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent infectious human diseases globally. IAV continues to challenge existing vaccines and antiviral drugs via its ability to evolve constantly. It is critical to identify the molecular determinants of IAV pathogenesis to understand the basis of flu severity in different populations and design improved antiviral strategies. In recent years, acetylation has been identified as one of the determinants of IAV pathogenesis. Acetylation was originally discovered as an epigenetic protein modification of histones. But, it is now known to be one of the ubiquitous protein modifications of both histones and non-histone proteins and a determinant of proteome complexity. Since our first observation in 2007, significant progress has been made in understanding the role of acetylation during IAV infection. Now, it is becoming clearer that acetylation plays a pro-IAV function via at least three mechanisms: (1) by reducing the host's sensing of IAV infection, (2) by dampening the host's innate antiviral response against IAV, and (3) by aiding the stability and function of viral and host proteins during IAV infection. In turn, IAV antagonizes the host deacetylases, which erase acetylation, to facilitate its replication. This review provides an overview of the research progress made on this subject so far and outlines research prospects for the significance of IAV-acetylation interplay.
Topics: Humans; Acetylation; Histones; Epigenesis, Genetic; Influenza A virus; Influenza, Human; Antiviral Agents
PubMed: 38257831
DOI: 10.3390/v16010131 -
Cell Chemical Biology Jan 2024Methylation is one of the critical modifications that regulates numerous biological processes. Guanine capping and methylation at the 7 position (mG) have been shown to... (Review)
Review
Methylation is one of the critical modifications that regulates numerous biological processes. Guanine capping and methylation at the 7 position (mG) have been shown to mature mRNA for increased RNA stability and translational efficiency. The mG capped cap0 RNA remains immature and requires additional methylation at the first nucleotide (N1-2'-O-Me), designated as cap1, to achieve full maturation. This cap1 RNA with N1-2'-O-Me prevents its recognition by innate immune sensors as non-self. Viruses have also evolved various strategies to produce self-like capped RNAs with the N1-2'-O-Me that potentially evades the antiviral response and establishes an efficient replication. In this review, we focus on the importance of the presence of N1-2'-O-Me in viral RNAs and discuss the potential for drug development by targeting host and viral N1-2'-O-methyltransferases.
Topics: Antiviral Agents; Methylation; Methyltransferases; RNA Caps; RNA, Messenger; RNA, Viral; Drug Design; Humans
PubMed: 38091983
DOI: 10.1016/j.chembiol.2023.11.011 -
JCI Insight Sep 2023The intricate interplay between maternal immune response to SARS-CoV-2 and the transfer of protective factors to the fetus remains unclear. By analyzing mother-neonate...
The intricate interplay between maternal immune response to SARS-CoV-2 and the transfer of protective factors to the fetus remains unclear. By analyzing mother-neonate dyads from second and third trimester SARS-CoV-2 infections, our study shows that neutralizing antibodies (NAbs) are infrequently detected in cord blood. We uncovered that this is due to impaired IgG-NAb placental transfer in symptomatic infection and to the predominance of maternal SARS-CoV-2 NAbs of the IgA and IgM isotypes, which are prevented from crossing the placenta. Crucially, the balance between maternal antiviral response and transplacental transfer of IgG-NAbs appears to hinge on IL-6 and IL-10 produced in response to SARS-CoV-2 infection. In addition, asymptomatic maternal infection was associated with expansion of anti-SARS-CoV-2 IgM and NK cell frequency. Our findings identify a protective role for IgA/IgM-NAbs in gestational SARS-CoV-2 infection and open the possibility that the maternal immune response to SARS-CoV-2 infection might benefit the neonate in 2 ways, first by skewing maternal immune response toward immediate viral clearance, and second by endowing the neonate with protective mechanisms to curtail horizontal viral transmission in the critical postnatal period, via the priming of IgA/IgM-NAbs to be transferred by the breast milk and via NK cell expansion in the neonate.
Topics: Pregnancy; Infant, Newborn; Humans; Female; COVID-19; SARS-CoV-2; Placenta; Antibodies, Neutralizing; Asymptomatic Infections; Immunoglobulin A; Immunoglobulin M; Antiviral Agents; Immunoglobulin G
PubMed: 37490342
DOI: 10.1172/jci.insight.167140