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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 -
Frontiers in Immunology 2022The central nervous system (CNS) is a constitutive structure of various cell types conserved by anatomical barriers. Many of the major CNS cell-type populations... (Review)
Review
The central nervous system (CNS) is a constitutive structure of various cell types conserved by anatomical barriers. Many of the major CNS cell-type populations distributed across the different brain regions are targets for several neurotropic viruses. Numerous studies have demonstrated that viral susceptibility within the CNS is not absolute and initiates a cell-type specific antiviral defence response. Neurons, astrocytes, and microglial cells are among the major resident cell populations within the CNS and are all equipped to sense viral infection and induce a relative antiviral response mostly through type I IFN production, however, not all these cell types adopt a similar antiviral strategy. Rising evidence has suggested a diversity regarding IFN production and responsiveness based on the cell type/sub type, regional distinction and cell`s developmental state which could shape distinct antiviral signatures. Among CNS resident cell types, neurons are of the highest priority to defend against the invading virus due to their poor renewable nature. Therefore, infected and uninfected glial cells tend to play more dominant antiviral roles during a viral infection and have been found to be the major CNS IFN producers. Alternatively, neuronal cells do play an active part during antiviral responses but may adopt differential strategies in addition to induction of a typical type I IFN response, to minimize the chance of cellular damage. Heterogeneity observed in neuronal IFN responsiveness may be partially explained by their altered ISGs and/or lower STATS expression levels, however, further studies are required to fully elucidate the specificity of the acquired antiviral responses by distinct CNS cell types.
Topics: Central Nervous System; Astrocytes; Microglia; Neuroglia; Antiviral Agents
PubMed: 36458002
DOI: 10.3389/fimmu.2022.1044721 -
Journal of Virology Nov 2022Human norovirus (HNoV) accounts for one-fifth of all acute viral gastroenteritis worldwide and an economic burden of ~$60 billion globally. The lack of treatment options...
Human norovirus (HNoV) accounts for one-fifth of all acute viral gastroenteritis worldwide and an economic burden of ~$60 billion globally. The lack of treatment options against HNoV is in part due to the lack of cultivation systems. Recently, a model of infection in biopsy-derived human intestinal enteroids (HIE) has been described: 3D-HIE are first dispersed in 2D-monolayers and differentiated prior to infection, resulting in a labor-intensive, time-consuming procedure. Here, we present an alternative protocol for HNoV infection of 3D-HIE. We found that 3D-HIE differentiated as efficiently as 2D-monolayers. In addition, immunofluorescence-based quantification of UEA-1, a lectin that stains the villus brush border, revealed that ~80% of differentiated 3D-HIE spontaneously undergo polarity inversion, allowing for viral infection without the need for microinjection. Infection with HNoV GII.4-positive stool samples attained a fold-increase over inoculum of ~2 Log at 2 days postinfection or up to 3.5 Log when ruxolitinib, a JAK1/2-inhibitor, was added. Treatment of GII.4-infected 3D-HIE with the polymerase inhibitor 2'--Methylcytidine (2CMC) and other antivirals showed a reduction in viral infection, suggesting that 3D-HIE are an excellent platform to test anti-infectives. The transcriptional host response to HNoV was then investigated by RNA sequencing in infected versus uninfected 3D-HIE in the presence of ruxolitinib to focus on virus-associated signatures while limiting interferon-stimulated gene signatures. The analysis revealed upregulated hormone and neurotransmitter signal transduction pathways and downregulated glycolysis and hypoxia-response pathways upon HNoV infection. Overall, 3D-HIE have proven to be a highly robust model to study HNoV infection, screen antivirals, and to investigate the host response to HNoV infection. The human norovirus (HNoV) clinical and socio-economic impact calls for immediate action in the development of anti-infectives. Physiologically relevant models are hence needed to study HNoV biology, tropism, and mechanisms of viral-associated disease, and also as a platform to identify antiviral agents. Biopsy-derived human intestinal enteroids are a biomimetic of the intestinal epithelium and were recently described as a model that supports HNoV infection. However, the established protocol is time-consuming and labor-intensive. Therefore, we sought to develop a simplified and robust alternative model of infection in 3D enteroids that undergoes differentiation and spontaneous polarity inversion. Advantages of this model are the shorter experimental time, better infection yield, and spatial integrity of the intestinal epithelium. This model is potentially suitable for the study of other pathogens that infect intestinal cells from the apical surface but also for unraveling the interactions between intestinal epithelium and indigenous bacteria of the human microbiome.
Topics: Humans; Norovirus; Pyrazoles; Caliciviridae Infections; Gastroenteritis; Antiviral Agents
PubMed: 36342297
DOI: 10.1128/jvi.00855-22 -
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 -
Gut and Liver Nov 2016Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts... (Review)
Review
Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens.
Topics: Antiviral Agents; Drug Resistance, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Treatment Failure
PubMed: 27784846
DOI: 10.5009/gnl15573 -
Virulence Dec 2022Influenza A virus (IAV) is an infectious pathogen, threatening the population and public safety with its epidemics. Therefore, it is essential to better understand... (Review)
Review
Influenza A virus (IAV) is an infectious pathogen, threatening the population and public safety with its epidemics. Therefore, it is essential to better understand influenza virus biology to develop efficient strategies against its pathogenicity. Autophagy is an important cellular process to maintain cellular homeostasis by cleaning up the hazardous substrates in lysosome. Accumulating research has also suggested that autophagy is a critical mechanism in host defense responses against IAV infection by degrading viral particles and activating innate or acquired immunity to induce viral clearance. However, IAV has conversely hijacked autophagy to strengthen virus infection by blocking autophagy maturation and further interfering host antiviral signalling to promote viral replication. Therefore, how the battle for autophagy between host and IAV is carried out need to be known. In this review, we describe the role of autophagy in host defence and IAV survival, and summarize the role of influenza proteins in subverting the autophagic process as well as then concentrate on how host utilize antiviral function of autophagy to prevent IAV infection.
Topics: Antiviral Agents; Autophagy; Host-Pathogen Interactions; Humans; Immunity, Innate; Influenza A virus; Influenza, Human; Virus Replication
PubMed: 34967267
DOI: 10.1080/21505594.2021.2014680 -
Journal of Gastroenterology May 2018Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is... (Review)
Review
Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is high and is moreover associated with a poor prognosis. In liver transplantation patients with HCV infection, recurrent HCV infection is universal, and re-infected HCV causes rapid progression of liver fibrosis and graft loss. Additionally, in patients with HCV and human immunodeficiency virus (HIV) co-infection, liver fibrosis progresses rapidly. Thus, there is an acute need for prompt treatment of HCV infection in these special populations (i.e., hemodialysis, liver transplantation, HIV co-infection). However, until recently, the standard anti-HCV treatment involved the use of interferon-based therapy. In these special populations, interferon-based therapies could not achieve a high rate of sustained viral response and moreover were associated with a higher rate of adverse events. With the development of novel direct-acting antivirals (DAAs), the landscape of anti-HCV therapy for special populations has changed dramatically. Indeed, in special populations treated with interferon-free DAAs, the sustained viral response rate was above 90%, with a lower incidence and severity of adverse events.
Topics: Antiviral Agents; Coinfection; Drug Therapy, Combination; HIV Infections; Hepatitis C; Humans; Immunocompromised Host; Interferons; Liver Transplantation; Postoperative Period; Protease Inhibitors; Recurrence; Renal Dialysis; Renal Insufficiency, Chronic; Ribavirin
PubMed: 29299684
DOI: 10.1007/s00535-017-1427-x -
Frontiers in Immunology 2022The chronic infection with hepatitis B virus (HBV) is an important health problem that affects millions of people worldwide. Current therapies for HBV always suffer from... (Review)
Review
The chronic infection with hepatitis B virus (HBV) is an important health problem that affects millions of people worldwide. Current therapies for HBV always suffer from a poor response rate, common side effects, and the need for lifelong treatment. Novel therapeutic targets are expected. Interestingly, non-canonical structures of nucleic acids play crucial roles in the regulation of gene expression. Especially the formation of G-quadruplexes (G4s) in G-rich strands has been demonstrated to affect many bioprocesses including replication, transcription, and translation, showing great potential as targets in anticancer and antiviral therapies. In this review, we summarize recent antiviral studies about G4s and discuss the potential roles of G4 structures in antiviral therapy for HBV.
Topics: Humans; G-Quadruplexes; Hepatitis B virus; Antiviral Agents
PubMed: 36591216
DOI: 10.3389/fimmu.2022.1091873 -
Frontiers in Immunology 2022The adaptive immune response induced by SARS-CoV-2 plays a key role in the antiviral process and can protect the body from the threat of infection for a certain period... (Review)
Review
The adaptive immune response induced by SARS-CoV-2 plays a key role in the antiviral process and can protect the body from the threat of infection for a certain period of time. However, owing to the limitations of clinical studies, the antiviral mechanisms, protective thresholds, and persistence of the immune memory of adaptive immune responses remain unclear. This review summarizes existing research models for SARS-CoV-2 and elaborates on the advantages of animal models in simulating the clinical symptoms of COVID-19 in humans. In addition, we systematically summarize the research progress on the SARS-CoV-2 adaptive immune response and the remaining key issues, as well as the application and prospects of animal models in this field. This paper provides direction for in-depth analysis of the anti-SARS-CoV-2 mechanism of the adaptive immune response and lays the foundation for the development and application of vaccines and drugs.
Topics: Adaptive Immunity; Animals; Antiviral Agents; COVID-19; Humans; Models, Animal; SARS-CoV-2
PubMed: 36189203
DOI: 10.3389/fimmu.2022.993754 -
Antiviral Research Sep 2023Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that causes COVID-19 disease, with an estimated global mortality of approximately 2%....
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that causes COVID-19 disease, with an estimated global mortality of approximately 2%. While global response strategies, which are predominantly reliant on regular vaccinations, have shifted from zero COVID to living with COVID, there is a distinct lack of broad-spectrum direct acting antiviral therapies that maintain efficacy across evolving SARS-CoV-2 variants of concern. This is of most concern for immunocompromised and immunosuppressed individuals who lack robust immune responses following vaccination, and others at risk for severe COVID and long-COVID. RNA interference (RNAi) therapeutics induced by short interfering RNAs (siRNAs) offer a promising antiviral treatment option, with broad-spectrum antiviral capabilities unparalleled by current antiviral therapeutics and a high genetic barrier to antiviral escape. Here we describe novel siRNAs, targeting highly conserved regions of the SARS-CoV-1 and 2 genome of both human and animal species, with multi-variant antiviral potency against eight SARS-CoV-2 lineages - Ancestral VIC01, Alpha, Beta, Gamma, Delta, Zeta, Kappa and Omicron. Treatment with our siRNA resulted in significant protection against virus-mediated cell death in vitro, with >97% cell survival (P < 0.0001), and corresponding reductions of viral nucleocapsid RNA of up to 99.9% (P < 0.0001). When compared to antivirals; Sotrovimab and Remdesivir, the siRNAs demonstrated a more potent antiviral effect and similarly, when multiplexing siRNAs to target different viral regions simultaneously, an increased antiviral effect was observed compared to individual siRNA treatments (P < 0.0001). These results demonstrate the potential for a highly effective broad-spectrum direct acting antiviral against multiple SARS-CoV-2 variants, including variants resistant to antivirals and vaccine generated neutralizing antibodies.
Topics: Animals; Humans; RNA, Small Interfering; SARS-CoV-2; Antiviral Agents; Post-Acute COVID-19 Syndrome; COVID-19; Hepatitis C, Chronic; Antibodies, Neutralizing; Antibodies, Viral; Spike Glycoprotein, Coronavirus
PubMed: 37478918
DOI: 10.1016/j.antiviral.2023.105677