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Current Opinion in Immunology Aug 2022Viral proteins fold into a variety of structures as they perform their functions. Structure-based vaccine design aims to exploit knowledge of an antigen's architecture... (Review)
Review
Viral proteins fold into a variety of structures as they perform their functions. Structure-based vaccine design aims to exploit knowledge of an antigen's architecture to stabilize it in a vulnerable conformation. We summarize the general principles of structure-based vaccine design, with a focus on the major types of sequence modifications: proline, disulfide, cavity-filling, electrostatic and hydrogen-bond substitution, as well as domain deletion. We then review recent applications of these principles to vaccine-design efforts across five viral families: Coronaviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Filoviridae. Outstanding challenges include continued application of proven design principles to pathogens of interest, as well as development of new strategies for those pathogens that resist traditional techniques.
Topics: Coronaviridae; Filoviridae; Humans; Orthomyxoviridae; Paramyxoviridae; Pneumovirinae; Vaccine Development; Viral Proteins; Viral Vaccines
PubMed: 35598506
DOI: 10.1016/j.coi.2022.102209 -
Respirology (Carlton, Vic.) Nov 2021
Topics: Humans; Interleukin-17; Lung; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Virus Diseases
PubMed: 34580948
DOI: 10.1111/resp.14158 -
Microbial Genomics Sep 2023Respiratory syncytial virus (RSV), or human orthopneumovirus, is a major cause of acute lower respiratory infection (ALRI), particularly in young children, causing...
Respiratory syncytial virus (RSV), or human orthopneumovirus, is a major cause of acute lower respiratory infection (ALRI), particularly in young children, causing significant morbidity and mortality. We used pathogen genomics to characterize the population structure and genetic signatures of RSV isolates circulating in children in New South Wales between 2016 and 2018 and to understand the evolutionary dynamics of these strains in the context of publicly available RSV genomes from the region and globally. Whole-genome phylogenetic analysis demonstrated the co-circulation of a few major RSV clades in the paediatric population from Sydney. The whole-genome-based genotypes A23 (RSV-A ON1-like genotype) and B6 (RSV-B BA9-like genotype) were the predominant RSV-A and RSV-B genotypes circulating during the study period, respectively. These genotypes were characterized with high levels of diversity of predicted N- and O-linked glycosylation patterns in both the G and F glycoproteins. Interestingly, a novel 72-nucleotide triplication in the sequence that corresponds to the C-terminal region of the gene was identified in four of the A23 genotype sequenced in this study. Consistently, the population dynamics analysis demonstrated a continuous increase in the effective population size of A23 and B6 genotypes globally. Further investigations including functional mapping of mutations and identifying the impact of sequence changes on virus fitness are highly required. This study highlights the potential impact of an integrated approach that uses WG-based phylogeny and studying selective pressure events in understanding the emergence and dissemination of RSV genotypes.
Topics: Child; Humans; Child, Preschool; Phylogeny; Genomics; Respiratory Syncytial Viruses; Genotype; Australia; Respiratory Tract Infections
PubMed: 37656160
DOI: 10.1099/mgen.0.001095 -
Viruses Dec 2021Pneumoviruses include pathogenic human and animal viruses, the most known and studied being the human respiratory syncytial virus (hRSV) and the metapneumovirus (hMPV),... (Review)
Review
Pneumoviruses include pathogenic human and animal viruses, the most known and studied being the human respiratory syncytial virus (hRSV) and the metapneumovirus (hMPV), which are the major cause of severe acute respiratory tract illness in young children worldwide, and main pathogens infecting elderly and immune-compromised people. The transcription and replication of these viruses take place in specific cytoplasmic inclusions called inclusion bodies (IBs). These activities depend on viral polymerase L, associated with its cofactor phosphoprotein P, for the recognition of the viral RNA genome encapsidated by the nucleoprotein N, forming the nucleocapsid (NC). The polymerase activities rely on diverse transient protein-protein interactions orchestrated by P playing the hub role. Among these interactions, P interacts with the NC to recruit L to the genome. The P protein also plays the role of chaperone to maintain the neosynthesized N monomeric and RNA-free (called N) before specific encapsidation of the viral genome and antigenome. This review aims at giving an overview of recent structural information obtained for hRSV and hMPV P, N, and more specifically for P-NC and N-P complexes that pave the way for the rational design of new antivirals against those viruses.
Topics: Animals; Antiviral Agents; Drug Design; Humans; Metapneumovirus; Models, Molecular; Nucleocapsid Proteins; Paramyxoviridae Infections; Phosphoproteins; Protein Binding; Protein Conformation; RNA, Viral; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Transcription, Genetic; Viral Proteins; Virus Replication
PubMed: 34960719
DOI: 10.3390/v13122449 -
The New England Journal of Medicine Feb 2022
Topics: Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 35172061
DOI: 10.1056/NEJMe2118465 -
Sub-cellular Biochemistry 2018Human respiratory syncytial virus (HRSV) is a non-segmented negative stranded RNA virus and is recognized as the most important viral agent of lower respiratory tract... (Review)
Review
Human respiratory syncytial virus (HRSV) is a non-segmented negative stranded RNA virus and is recognized as the most important viral agent of lower respiratory tract infection worldwide, responsible for up to 199,000 deaths each year. The only FDA-approved regime to prevent HRSV-mediated disease is pre-exposure administration of a humanized HRSV-specific monoclonal antibody, which although being effective, is not in widespread usage due to its cost. No HRSV vaccine exists and so there remains a strong need for alternative and complementary anti-HRSV therapies. The HRSV M2-1 protein is a transcription factor and represents an attractive target for the development of antiviral compounds, based on its essential role in the viral replication cycle. To this end, a detailed analysis of M2-1 structure and functions will aid in identifying rational targets for structure-based antiviral drug design that can be developed in future translational research. Here we present an overview of the current understanding of the structure and function of HRSV M2-1, drawing on additional information derived from its structural homologues from other related viruses.
Topics: Humans; Respiratory Syncytial Virus, Human; Structure-Activity Relationship; Viral Proteins; Virus Replication
PubMed: 29900500
DOI: 10.1007/978-981-10-8456-0_11 -
Nature Sep 2023
Topics: Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 37758879
DOI: 10.1038/d41586-023-02962-2 -
European Journal of Pharmaceutical... Dec 2023Chronic respiratory diseases and infections are among the largest contributors to death globally, many of which still have no cure, including chronic obstructive... (Review)
Review
Chronic respiratory diseases and infections are among the largest contributors to death globally, many of which still have no cure, including chronic obstructive pulmonary disorder, idiopathic pulmonary fibrosis, and respiratory syncytial virus among others. Pulmonary therapeutics afford untapped potential for treating lung infection and disease through direct delivery to the site of action. However, the ability to innovate new therapeutic paradigms for respiratory diseases will rely on modeling the human lung microenvironment and including key cellular interactions that drive disease. One key feature of the lung microenvironment is the air-liquid interface (ALI). ALI interface modeling techniques, using cell-culture inserts, organoids, microfluidics, and precision lung slices (PCLS), are rapidly developing; however, one major component of these models is lacking-innate immune cell populations. Macrophages, neutrophils, and dendritic cells, among others, represent key lung cell populations, acting as the first responders during lung infection or injury. Innate immune cells respond to and modulate stromal cells and bridge the gap between the innate and adaptive immune system, controlling the bodies response to foreign pathogens and debris. In this article, we review the current state of ALI culture systems with a focus on innate immune cells and suggest ways to build on current models to add complexity and relevant immune cell populations.
Topics: Humans; Lung; Pulmonary Disease, Chronic Obstructive; Macrophages; Respiratory Syncytial Virus, Human; Immunity; Immunity, Innate
PubMed: 37770004
DOI: 10.1016/j.ejps.2023.106596 -
Nature Communications Aug 2021Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV... (Clinical Trial)
Clinical Trial
Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.
Topics: Aged; Antigenic Variation; Female; Genetic Variation; Humans; Infant; Male; Mutation, Missense; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Viral Proteins; Virus Replication
PubMed: 34446722
DOI: 10.1038/s41467-021-25265-4 -
Pneumologie (Stuttgart, Germany) Jun 2020RSV induces an acute viral disease with involvement of the respiratory tract. It can be notably life-threatening for infants but also for older adults. New RSV-subtypes... (Review)
Review
RSV induces an acute viral disease with involvement of the respiratory tract. It can be notably life-threatening for infants but also for older adults. New RSV-subtypes are constantly evolving globally. The knowledge about epidemiology, hygiene measures, diagnostics and clinical feature is essential not only for the paediatrician. Vaccines or specific therapeutics are still missing. This article gives an overview with focus on RSV in adults. In addition, molecular pathological characteristics of the virus are explained, research approaches concerning vaccines and therapeutics are mentioned and current problems in management are discussed.
Topics: Humans; Respiratory Insufficiency; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 32557509
DOI: 10.1055/a-0853-2881