Antiviral research最新文献

{"title":"Anti-HBc mirrors the activation of HBV-specific CD8+ T cell immune response and exhibits a direct effect on HBV control","authors":"Guofu Ye ,&nbsp;Chengcong Chen ,&nbsp;Yongjun Zhou ,&nbsp;Libo Tang ,&nbsp;Jianzhong Cai ,&nbsp;Yiyan Huang ,&nbsp;Jiayue Yang ,&nbsp;Yaoting Feng ,&nbsp;Liangxing Chen ,&nbsp;Yuhao Wang ,&nbsp;Yanchen Ma ,&nbsp;Guanfeng Lin ,&nbsp;Yingsong Wu ,&nbsp;Xiaotao Jiang ,&nbsp;Jinlin Hou ,&nbsp;Yongyin Li","doi":"10.1016/j.antiviral.2024.105975","DOIUrl":"10.1016/j.antiviral.2024.105975","url":null,"abstract":"<div><h3>Background</h3><p>Hepatitis B core antibody (anti-HBc) is commonly present in patients with chronic hepatitis B virus (HBV) infection and serves as a marker of humoral immunity. Herein, we aim to investigate the correlation between anti-HBc and antiviral immune response and its putative role in HBV control.</p></div><div><h3>Methods</h3><p>Quantitative anti-HBc and levels of anti-HBc subtypes were measured in chronic hepatitis B (CHB) patients. The effects of anti-HBc on immune cells and HBV replication were evaluated using the HBV mouse models and human hepatoma cell lines.</p></div><div><h3>Results</h3><p>Baseline levels of IgG1 and IgG3 anti-HBc were elevated in CHB patients with favorable treatment response, and correlated with the virological response observed at week 52. Additionally, increased levels of IgM and IgG1 anti-HBc were observed exclusively in CHB patients with liver inflammation. Notably, significant correlations were identified between quantitative levels of anti-HBc and the frequencies of HBcAg-specific CD8⁺ T cells. Intriguingly, HBcAg efficiently activates T cells aided by B cells <em>in vitro</em> experiments. Moreover, anti-HBc inhibits HBV replication either by a direct effect or through complement-mediated cytotoxicity in HBV-producing cell lines.</p></div><div><h3>Conclusions</h3><p>Anti-HBc reflects the activation of an HBV-specific CD8⁺ T cell immune response and may have anti-HBV activity.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105975"},"PeriodicalIF":4.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-d-N4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus","authors":"Kei Konishi ,&nbsp;Shinji Kusakabe ,&nbsp;Nijiho Kawaguchi ,&nbsp;Takao Shishido ,&nbsp;Naoto Ito ,&nbsp;Michiko Harada ,&nbsp;Satoshi Inoue ,&nbsp;Ken Maeda ,&nbsp;William W. Hall ,&nbsp;Yasuko Orba ,&nbsp;Hirofumi Sawa ,&nbsp;Michihito Sasaki ,&nbsp;Akihiko Sato","doi":"10.1016/j.antiviral.2024.105977","DOIUrl":"10.1016/j.antiviral.2024.105977","url":null,"abstract":"<div><p>Rabies is a fatal neurological disorder caused by rabies virus (RABV) infection. Approximately 60,000 patients die from rabies annually, and there are no effective treatments for this disease. Nucleoside analogs are employed as antiviral drugs based on their broad antiviral spectrum, and certain nucleoside analogs have been reported to exhibit anti-RABV activity. The nucleoside analog β-<span>d</span>-<em>N</em>⁴-hydroxycytidine (NHC) has antiviral effects against a range of RNA viruses. Molnupiravir (MPV), a prodrug of NHC, is clinically used as an oral antiviral drug for coronavirus infections. Despite its broad-spectrum activity, the antiviral activity of NHC against RABV remains unclear. In this study, we reveal that NHC exhibits comparable <em>in vitro</em> anti-RABV activity as ribavirin and favipiravir (also known as T-705) with a 90% effective concentration of 6 μM in mouse neuroblastoma cells. NHC reduced viral loads in neuronal and nonneuronal cells in a dose-dependent manner. Both laboratory and field RABVs (fixed and street strains, respectively) were susceptible to NHC. However, no increase in survival or reduction in viral titers in the brain was observed in RABV-infected mice treated prophylactically with MPV. These findings highlight the potential and challenges of NHC in the treatment of RABV infection.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"229 ","pages":"Article 105977"},"PeriodicalIF":4.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activating adaptive immunity by bispecific, T-cell engager antibodies bridging infected and immune-effector cells is a promising novel therapy for chronic hepatitis B","authors":"Zhe Xie ,&nbsp;Ulrike Protzer","doi":"10.1016/j.antiviral.2024.105972","DOIUrl":"10.1016/j.antiviral.2024.105972","url":null,"abstract":"<div><p>Bispecific antibodies (bsAbs) are engineered immunoglobulins that combine two different antigen-binding sites in one molecule. BsAbs can be divided into two molecular formats: IgG-like and non-IgG-like antibodies. Structural elements of each format have implications for engaging the immune system. T cell engager antibodies (TCEs) are bsAbs designed to engage T cells with target cells. TCEs can be applied not only in cancer but also in infectious disease therapy to activate T-cell responses. In this review, we focus on current literature on the design and use of bsAbs as an innovative strategy to enhance adaptive antiviral immune responses. We summarized the novel T cell-related immunotherapies with a focus on TCEs, that are developed for the treatment of chronic hepatitis B. Chronic infection with the hepatitis B virus (HBV) had a death toll of 1.1 million humans in 2022, mainly due to liver cirrhosis and hepatocellular carcinoma developing in the more than 250 million humans chronically infected. A curative treatment approach for chronic hepatitis B is lacking. Combining antiviral therapy with immune therapies activating T-cell responses is regarded as the most promising therapeutic approach to curing HBV and preventing the sequelae of chronic infection. Attracting functionally intact T cells that are not HBV-specific and, therefore, have not yet been exposed to regulatory mechanisms and activating those at the target site in the liver is a very interesting therapeutic approach that could be achieved by TCEs. Thus, TCEs redirecting T cells toward HBV-positive cells represent a promising strategy for treating chronic hepatitis B and HBV-associated hepatocellular carcinoma.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"229 ","pages":"Article 105972"},"PeriodicalIF":4.5,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001815/pdfft?md5=6ed81d63d687c839a00f0fad45d598b3&pid=1-s2.0-S0166354224001815-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of human cytomegalovirus entry into mucosal epithelial cells","authors":"Li He ,&nbsp;Laura Hertel ,&nbsp;Claire D. James ,&nbsp;Iain M. Morgan ,&nbsp;Aloysius J. Klingelhutz ,&nbsp;Tong-Ming Fu ,&nbsp;Lawrence M. Kauvar ,&nbsp;Michael A. McVoy","doi":"10.1016/j.antiviral.2024.105971","DOIUrl":"10.1016/j.antiviral.2024.105971","url":null,"abstract":"<div><p>Human cytomegalovirus (CMV) causes serious developmental disabilities in newborns infected <em>in utero</em> following oral acquisition by the mother. Thus, neutralizing antibodies in maternal saliva have potential to prevent maternal infection and, consequently, fetal transmission and disease. Based on standard cell culture models, CMV entry mediators (and hence neutralizing targets) are cell type-dependent: entry into fibroblasts requires glycoprotein B (gB) and a trimeric complex (TC) of glycoproteins H, L, and O, whereas endothelial and epithelial cell entry additionally requires a pentameric complex (PC) of glycoproteins H and L with UL128, UL130, and UL131A. However, as the mediators of mucosal cell entry and the potential impact of cellular differentiation remained unclear, the present studies utilized mutant viruses, neutralizing antibodies, and soluble TC-receptor to determine the entry mediators required for infection of mucocutaneus cell lines and primary tonsil epithelial cells. Entry into undifferentiated cells was largely PC-dependent, but PC-independent entry could be induced by differentiation. TC-independent entry was also observed and varied by cell line and differentiation. Infection of primary tonsil cells from some donors was entirely TC-independent. In contrast, an antibody to gB or disruption of virion attachment using heparin blocked entry into all cells. These findings indicate that CMV entry into the spectrum of cell types encountered <em>in vivo</em> is likely to be more complex than has been suggested by standard cell culture models and may be influenced by the relative abundance of virion envelope glycoprotein complexes as well as by cell type, tissue of origin, and state of differentiation.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105971"},"PeriodicalIF":4.5,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nirmatrelvir and molnupiravir maintain potent in vitro and in vivo antiviral activity against circulating SARS-CoV-2 omicron subvariants","authors":"Romel Rosales ,&nbsp;Briana L. McGovern ,&nbsp;M. Luis Rodriguez ,&nbsp;Rocio Leiva-Rebollo ,&nbsp;Randy Diaz-Tapia ,&nbsp;Jared Benjamin ,&nbsp;Devendra K. Rai ,&nbsp;Rhonda D. Cardin ,&nbsp;Annaliesa S. Anderson ,&nbsp;Emilia Mia Sordillo ,&nbsp;Harm van Bakel ,&nbsp;Viviana Simon ,&nbsp;Adolfo García-Sastre ,&nbsp;Kris M. White","doi":"10.1016/j.antiviral.2024.105970","DOIUrl":"10.1016/j.antiviral.2024.105970","url":null,"abstract":"<div><p>Variants of SARS-CoV-2 pose significant challenges in public health due to their increased transmissibility and ability to evade natural immunity, vaccine protection, and monoclonal antibody therapeutics. The emergence of the highly transmissible Omicron variant and subsequent subvariants, characterized by an extensive array of over 32 mutations within the spike protein, intensifies concerns regarding vaccine evasion. In response, multiple antiviral therapeutics have received FDA emergency use approval, targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro) regions, known to have relatively fewer mutations across novel variants. In this study, we evaluated the efficacy of nirmatrelvir (PF-07321332) and other clinically significant SARS-CoV-2 antivirals against a diverse panel of SARS-CoV-2 variants, encompassing the newly identified Omicron subvariants XBB1.5 and JN.1, using live-virus antiviral assays. Our findings demonstrate that while the last Omicron subvariants exhibited heightened pathogenicity in our animal model, nirmatrelvir and other clinically relevant antivirals consistently maintained their efficacy against all tested variants, including the XBB1.5 subvariant.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105970"},"PeriodicalIF":4.5,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly specific SARS-CoV-2 main protease (Mpro) mutations against the clinical antiviral ensitrelvir selected in a safe, VSV-based system","authors":"Stefanie Rauch ,&nbsp;Francesco Costacurta ,&nbsp;Helge Schöppe ,&nbsp;Ju-Yi Peng ,&nbsp;David Bante ,&nbsp;Ela Emilie Erisoez ,&nbsp;Bernhard Sprenger ,&nbsp;Xi He ,&nbsp;Seyed Arad Moghadasi ,&nbsp;Laura Krismer ,&nbsp;Anna Sauerwein ,&nbsp;Anne Heberle ,&nbsp;Toni Rabensteiner ,&nbsp;Dai Wang ,&nbsp;Andreas Naschberger ,&nbsp;Theresia Dunzendorfer-Matt ,&nbsp;Teresa Kaserer ,&nbsp;Dorothee von Laer ,&nbsp;Emmanuel Heilmann","doi":"10.1016/j.antiviral.2024.105969","DOIUrl":"10.1016/j.antiviral.2024.105969","url":null,"abstract":"<div><p>In the SARS-CoV-2 pandemic, the so far two most effective approved antivirals are the protease inhibitors nirmatrelvir, in combination with ritonavir (Paxlovid) and ensitrelvir (Xocova). However, antivirals and indeed all antimicrobial drugs are sooner or later challenged by resistance mutations. Studying such mutations is essential for treatment decisions and pandemic preparedness. At the same time, generating resistant viruses to assess mutants is controversial, especially with pathogens of pandemic potential like SARS-CoV-2. To circumvent gain-of-function research with non-attenuated SARS-CoV-2, a previously developed safe system based on a chimeric vesicular stomatitis virus dependent on the SARS-CoV-2 main protease (VSV-M^pro) was used to select mutations against ensitrelvir. Ensitrelvir is clinically especially relevant due to its single-substance formulation, avoiding drug-drug interactions by the co-formulated CYP3A4 inhibitor ritonavir in Paxlovid. By treating VSV-M^pro with ensitrelvir, highly-specific resistant mutants against this inhibitor were selected, while being still fully or largely susceptible to nirmatrelvir. We then confirmed several ensitrelvir-specific mutants in gold standard enzymatic assays and SARS-CoV-2 replicons. These findings indicate that the two inhibitors can have distinct viral resistance profiles, which could determine treatment decisions.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 105969"},"PeriodicalIF":4.5,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001785/pdfft?md5=a8eb9488aa96706381e7d5e8ab142db9&pid=1-s2.0-S0166354224001785-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mimetic peptide of ACE2 protects against SARS-CoV-2 infection and decreases pulmonary inflammation related to COVID-19","authors":"Ernna H. Oliveira ,&nbsp;Ana C. Monteleone-Cassiano ,&nbsp;Lucas Tavares ,&nbsp;Jadson C. Santos ,&nbsp;Thais M. Lima ,&nbsp;Giovanni F. Gomes ,&nbsp;Pedro P. Tanaka ,&nbsp;Cintia J. Monteiro ,&nbsp;Matheus Munuera ,&nbsp;Sabrina S. Batah ,&nbsp;Alexandre T. Fabro ,&nbsp;Vitor M. Faça ,&nbsp;Ana P. Masson ,&nbsp;Eduardo A. Donadi ,&nbsp;Mariangela Dametto ,&nbsp;Rodrigo Bonacin ,&nbsp;Ronaldo B. Martins Jr. ,&nbsp;Eurico Arruda Neto ,&nbsp;Luis Lamberti P. daSilva ,&nbsp;Thiago M. Cunha ,&nbsp;Geraldo A. Passos","doi":"10.1016/j.antiviral.2024.105968","DOIUrl":"10.1016/j.antiviral.2024.105968","url":null,"abstract":"<div><p>Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22–46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells <em>in vitro</em>. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S¹ RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the <em>in vitro</em> viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against <em>in vivo</em> SARS-CoV-2 infection and is effective for the treatment of COVID-19.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"229 ","pages":"Article 105968"},"PeriodicalIF":4.5,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High throughput profiling identified PA-L106R amino acid substitution in A(H1N1)pdm09 influenza virus that confers reduced susceptibility to baloxavir in vitro","authors":"Dongdong Chen ,&nbsp;Wen Su ,&nbsp;Ka-Tim Choy ,&nbsp;Yan Sing Chu ,&nbsp;Chi Ho Lin ,&nbsp;Hui-Ling Yen","doi":"10.1016/j.antiviral.2024.105961","DOIUrl":"10.1016/j.antiviral.2024.105961","url":null,"abstract":"<div><p>Baloxavir acid (BXA) is a pan-influenza antiviral that targets the cap-dependent endonuclease of the polymerase acidic (PA) protein required for viral mRNA synthesis. To gain a comprehensive understanding on the molecular changes associated with reduced susceptibility to BXA and their fitness profile, we performed a deep mutational scanning at the PA endonuclease domain of an A (H1N1)pdm09 virus. The recombinant virus libraries were serially passaged <em>in vitro</em> under increasing concentrations of BXA followed by next-generation sequencing to monitor PA amino acid substitutions with increased detection frequencies. Enriched PA amino acid changes were each introduced into a recombinant A (H1N1)pdm09 virus to validate their effect on BXA susceptibility and viral replication fitness <em>in vitro</em>. The I38 T/M substitutions known to confer reduced susceptibility to BXA were invariably detected from recombinant virus libraries within 5 serial passages. In addition, we identified a novel L106R substitution that emerged in the third passage and conferred greater than 10-fold reduced susceptibility to BXA. PA-L106 is highly conserved among seasonal influenza A and B viruses. Compared to the wild-type virus, the L106R substitution resulted in reduced polymerase activity and a minor reduction of the peak viral load, suggesting the amino acid change may result in moderate fitness loss. Our results support the use of deep mutational scanning as a practical tool to elucidate genotype-phenotype relationships, including mapping amino acid substitutions with reduced susceptibility to antivirals.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"229 ","pages":"Article 105961"},"PeriodicalIF":4.5,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001700/pdfft?md5=4cdda98322443d54d142f930c2a1c7d6&pid=1-s2.0-S0166354224001700-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cold-adapted influenza vaccine carrying three repeats of a respiratory syncytial virus (RSV) fusion glycoprotein epitope site protects BALB/c mice and cotton rats against RSV infection","authors":"","doi":"10.1016/j.antiviral.2024.105960","DOIUrl":"10.1016/j.antiviral.2024.105960","url":null,"abstract":"<div><p>Respiratory syncytial virus is the major cause of respiratory viral infections, particularly in infants, immunocompromised populations, and the elderly (over 65 years old), the prevention of RSV infection has become a priority. In this study, we generated a chimeric influenza virus, termed LAIV/RSV/HA-3F, using reverse genetics technology which contained three repeats of the RSV fusion protein neutralizing epitope site II to the N terminal in the background of the hemagglutinin (HA) gene of cold adapted influenza vaccine A/California/7/2009 ca. LAIV/RSV/HA-3F exhibited cold-adapted (<em>ca</em>) and attenuated (<em>att</em>) phenotype. BALB/c mice immunized intranasally with LAIV/RSV/HA-3F showed robust immunogenicity, inducing viral-specific antibody responses against both influenza and RSV, eliciting RSV-specific humoral, cellular and mucosal immune responses. LAIV/RSV/HA-3F also conferred protection as indicated by reduced viral titers and improved lung histopathological alterations against live RSV virus challenge. Mechanismly, single-cell RNA sequencing (scRNA-seq) and single-cell T cell antigen receptor (TCR) sequencing were employed to characterize the immune responses triggered by chimeric RSV vaccine, displaying that LAIV/RSV/HA-3F provided protection mainly via interferon-γ (IFN-γ). Moreover, we found that LAIV/RSV/HA-3F significantly inhibited viral replication in the challenged lung and protected against subsequent RSV challenge in cotton rats without causing lung disease. Taken together, our findings demonstrated that LAIV/RSV/HA-3F has potential as a promising bivalent vaccine with dual purpose candidate for the prevention of influenza and RSV, and preclinical and clinical studies warrant further investigations.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"229 ","pages":"Article 105960"},"PeriodicalIF":4.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotypic and phenotypic susceptibility of emerging avian influenza A viruses to neuraminidase and cap-dependent endonuclease inhibitors","authors":"Konstantin Andreev ,&nbsp;Jeremy C. Jones ,&nbsp;Patrick Seiler ,&nbsp;Ahmed Kandeil ,&nbsp;Richard J. Webby ,&nbsp;Elena A. Govorkova","doi":"10.1016/j.antiviral.2024.105959","DOIUrl":"10.1016/j.antiviral.2024.105959","url":null,"abstract":"<div><p>Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened &gt;20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010–2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor, baloxavir, were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC₅₀s 3- to 4-fold lower than for other subtypes (median IC₅₀: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC₅₀ increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a &lt;3-fold decrease in the baloxavir EC₅₀ and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC₅₀ (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"229 ","pages":"Article 105959"},"PeriodicalIF":4.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001682/pdfft?md5=df565dc127586a81154eb964e3b672a1&pid=1-s2.0-S0166354224001682-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}