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The Lancet. Microbe Aug 2023
Topics: Humans; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections
PubMed: 37390835
DOI: 10.1016/S2666-5247(23)00195-7 -
Communications Biology Oct 2023The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap...
The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.
Topics: Respiratory Syncytial Virus, Human; RNA-Dependent RNA Polymerase; Protein Binding; RNA; Nucleotides
PubMed: 37865687
DOI: 10.1038/s42003-023-05451-4 -
Expert Review of Respiratory Medicine Aug 2017Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections (LRTI) in infants, the elderly, and the immunocompromised. Although the... (Review)
Review
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections (LRTI) in infants, the elderly, and the immunocompromised. Although the development of a RSV vaccine has been a priority for >50 years, there is still no vaccine available. Treatment of RSV LRTI has remained mostly supportive, i.e. hydration and oxygenation. Palivizumab and ribavirin are the only options currently available for prevention and treatment of RSV infection, but evidence suggests that they are not fully effective. This creates a significant unmet medical need for new therapeutics for prevention and treatment of RSV worldwide. Areas covered: This article reviews the antiviral drugs and monoclonal antibodies (mAb) for RSV that are in different stages of clinical development. Expert commentary: Over the last 10 years, new antiviral drugs and mAb have shown clinical promise against RSV, and may become available in the coming years. Although the RSV fusion protein has been the most popular target for inhibitors and mAbs, new approaches targeting other viral proteins have shown promising results. To overcome the emergence of RSV escape mutants, combination antiviral therapy may be explored in the future.
Topics: Aged; Aged, 80 and over; Antiviral Agents; Humans; Immunocompromised Host; Infant; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 28574729
DOI: 10.1080/17476348.2017.1338567 -
Jornal de Pediatria 2023To identify and assess the current evidence available about the costs of managing hospitalized pediatric patients diagnosed with Respiratory Syncytial Virus (RSV) and... (Review)
Review
OBJECTIVE
To identify and assess the current evidence available about the costs of managing hospitalized pediatric patients diagnosed with Respiratory Syncytial Virus (RSV) and Parainfluenza Virus Type 3 (PIV3) in upper-middle-income countries.
METHODS
The authors conducted a systematic review across seven key databases from database inception to July 2022. Costs extracted were converted into 2022 International Dollars using the Purchasing Power Parity-adjusted. PROSPERO identifier: CRD42020225757.
RESULTS
No eligible study for PIV3 was recovered. For RSV, cost analysis and COI studies were performed for populations in Colombia, China, Malaysia, and Mexico. Comparing the total economic impact, the lowest cost per patient at the pediatric ward was observed in Malaysia ($ 347.60), while the highest was in Colombia ($ 709.66). On the other hand, at pediatric ICU, the lowest cost was observed in China ($ 1068.26), while the highest was in Mexico ($ 3815.56). Although there is no consensus on the major cost driver, all included studies described that the medications (treatment) consumed over 30% of the total cost. A high rate of inappropriate prescription drugs was observed.
CONCLUSION
The present study highlighted how RSV infection represents a substantial economic burden to health care systems and to society. The findings of the included studies suggest a possible association between baseline risk status and expenditures. Moreover, it was observed that an important amount of the cost is destinated to treatments that have no evidence or support in most clinical practice guidelines.
Topics: Humans; Child; Infant; Developing Countries; Financial Stress; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Parainfluenza Virus 3, Human; Hospitalization
PubMed: 37247828
DOI: 10.1016/j.jped.2023.05.003 -
Virus Research May 2019Pneumoviruses represent a major public health burden across the world. Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV), two of the most recognizable... (Review)
Review
Pneumoviruses represent a major public health burden across the world. Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV), two of the most recognizable pediatric infectious agents, belong to this family. These viruses are enveloped with a non-segmented negative-sense RNA genome, and their replication occurs in specialized cytosolic organelles named inclusion bodies (IB). The critical role of IBs in replication of pneumoviruses has begun to be elucidated, and our current understanding suggests they are highly dynamic structures. From IBs, newly synthesized nucleocapsids are transported to assembly sites, potentially via the actin cytoskeleton, to be incorporated into nascent virions. Released virions, which generally contain one genome, can then diffuse in the extracellular environment to target new cells and reinitiate the process of infection. This is a challenging business for virions, which must face several risks including the extracellular immune responses. In addition, several recent studies suggest that successful infection may be achieved more rapidly by multiple, rather than single, genomic copies being deposited into a target cell. Interestingly, recent data indicate that pneumoviruses have several mechanisms that permit their transmission en bloc, i.e. transmission of multiple genomes at the same time. These mechanisms include the well-studied syncytia formation as well as the newly described formation of long actin-based intercellular extensions. These not only permit en bloc viral transmission, but also bypass assembly of complete virions. In this review we describe several aspects of en bloc viral transmission and how these mechanisms are reshaping our understanding of pneumovirus replication, assembly and spread.
Topics: Animals; Cell Line; Humans; Metapneumovirus; Mice; Paramyxoviridae Infections; Pneumovirus; RNA, Viral; Virion; Virus Assembly; Virus Replication
PubMed: 30844414
DOI: 10.1016/j.virusres.2019.03.002 -
Journal of Infection and Public Health 2016Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection during early childhood and is associated with a great burden on patients, parents,... (Meta-Analysis)
Meta-Analysis Review
Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection during early childhood and is associated with a great burden on patients, parents, and society. While no treatment is yet available, results from recent phase 2 clinical trials of cell-entry inhibitors and RSV vaccines are promising. To prepare for introduction of these novel therapeutics, good understanding of its molecular epidemiology and continuous RSV surveillance data are necessary. This paper provides an overview of RSV prevalence and genotype distribution in Iran from 1996 to 2013. This meta-analysis includes 21 published studies. In total, 775 (18.7%) of 4140 respiratory specimens were positive for RSV infection. The male-female ratio of RSV-positive patients was 1.5:1. Significant peaks of RSV infection were detected during the cold season (November-March). RSV infection was mainly observed in patients <2 years of age. Phylogenetic studies showed that genotypes GA1, GA2, GA5, and BA co-circulated in Iran in 2007-2013. This review highlights the necessity of introducing standard molecular surveillance programs to inform the epidemiological, clinical, and pathological characteristics of various RSV genotypes. Improved understanding of the molecular epidemiology will be useful for development of novel RSV therapeutics.
Topics: Age Factors; Female; Genotype; Humans; Iran; Male; Molecular Epidemiology; Phylogeny; Prevalence; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Seasons; Sex Distribution
PubMed: 26143136
DOI: 10.1016/j.jiph.2015.05.005 -
Seminars in Respiratory and Critical... Dec 2021Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more... (Review)
Review
Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.
Topics: Humans; Immunity; Influenza, Human; Respiratory Syncytial Virus, Human; Respiratory System
PubMed: 34918319
DOI: 10.1055/s-0041-1736459 -
The Journal of Infectious Diseases Aug 2022
Topics: Humans; Infection Control; N95 Respirators; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Viral Load
PubMed: 35535586
DOI: 10.1093/infdis/jiac197 -
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 -
Frontiers in Cellular and Infection... 2022Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections and responsible for a large proportion of mortality in children and the... (Review)
Review
Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections and responsible for a large proportion of mortality in children and the elderly. There are no licensed vaccines available to date. Prophylaxis and therapeutic RSV-specific antibodies are limited to populations at high risk owing to high cost and uncertain clinical value. Receptors and host factors are two determinants important for virus entry and establishment of infection . The identification and understanding of viral receptors and host factors can help us to gain insight into the pathogenesis of RSV infection. Herein, we reviewed receptors and host factors that have been reported thus far. RSV could bind to CX3C chemokine receptor 1 and heparan sulfate proteoglycans the G protein, and to nucleolin, insulin-like growth factor-1 receptor, epidermal growth factor, and intercellular adhesion molecule-1 the F protein. Seven host restriction factors and 13 host factors essential for RSV infection were reviewed. We characterized the functions and their roles in the life cycle of RSV, trying to provide an update on the information of RSV-related receptors and host factors.
Topics: Antibodies, Viral; Epidermal Growth Factor; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 35281439
DOI: 10.3389/fcimb.2022.858629