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International Journal of Molecular... May 2024In this paper, the characteristics of 40 so far described virophages-parasites of giant viruses-are given, and the similarities and differences between virophages and... (Review)
Review
Virophages, Satellite Viruses, Virophage Replication and Its Effects and Virophage Defence Mechanisms for Giant Virus Hosts and Giant Virus Defence Systems against Virophages.
In this paper, the characteristics of 40 so far described virophages-parasites of giant viruses-are given, and the similarities and differences between virophages and satellite viruses, which also, like virophages, require helper viruses for replication, are described. The replication of virophages taking place at a specific site-the viral particle factory of giant viruses-and its consequences are presented, and the defence mechanisms of virophages for giant virus hosts, as a protective action for giant virus hosts-protozoa and algae-are approximated. The defence systems of giant viruses against virophages were also presented, which are similar to the CRISPR/Cas defence system found in bacteria and in Archea. These facts, and related to the very specific biological features of virophages (specific site of replication, specific mechanisms of their defensive effects for giant virus hosts, defence systems in giant viruses against virophages), indicate that virophages, and their host giant viruses, are biological objects, forming a 'novelty' in biology.
Topics: Giant Viruses; Satellite Viruses; Virophages; Virus Replication; Gene Silencing
PubMed: 38892066
DOI: 10.3390/ijms25115878 -
Scientific Reports Jun 2024Occult hepatitis B virus infection (OBI) is characterized by the presence of HBV DNA in the absence of detectable HBsAg. OBI is an important risk factor for cirrhosis...
Occult hepatitis B virus infection (OBI) is characterized by the presence of HBV DNA in the absence of detectable HBsAg. OBI is an important risk factor for cirrhosis and hepatocellular carcinoma, but its pathogenesis has not been fully elucidated. Mutations in the HBV preS/S genes can lead to impaired secretion of either HBsAg or S-protein resulting in the accumulation of defective viruses or S protein in cells. In our previous work, the M133S mutation was present in the HBV S gene of maintenance hemodialysis (MHD) patients with OBI. In this study, we investigated the potential role of amino acid substitutions in S proteins in S protein production and secretion through the construction of mutant S gene plasmids, structural prediction, transcriptome sequencing analysis, and in vitro functional studies. Protein structure prediction showed that the S protein M133S mutant exhibited hydrophilic modifications, with greater aggregation and accumulation of the entire structure within the membrane phospholipid bilayer. Differential gene enrichment analysis of transcriptome sequencing data showed that differentially expressed genes were mainly concentrated in protein processing in the endoplasmic reticulum (ER). The expression of heat shock family proteins and ER chaperone molecules was significantly increased in the wild-type and mutant groups, whereas the expression of mitochondria-associated proteins was decreased. Immunofluorescence staining and protein blotting showed that the endoplasmic reticulum-associated protein PDI, the autophagy marker LC3, and the lysosome-associated protein LAMP2 co-localized with the S proteins in the wild-type and mutant strains, and their expression was increased. The mitochondria-associated TOMM20 protein was also co-expressed with the S protein, but expression was significantly reduced in the mutant. The M133S mutation in the S gene is expressed as a defective and misfolded protein that accumulates in the endoplasmic reticulum causing secretion-impaired endoplasmic reticulum stress, which in turn triggers mitochondrial autophagy and recruits lysosomes to fuse with the autophagosome, leading to mitochondrial clearance. This study preliminarily demonstrated that the mutation of M133S in the S gene can cause OBI and is associated with disease progression, providing a theoretical basis for the diagnosis and treatment of OBI.
Topics: Humans; Mitophagy; Renal Dialysis; Hepatitis B; Hepatitis B virus; Endoplasmic Reticulum Stress; Hepatitis B Surface Antigens; Male; Mutation; Female; Middle Aged; Viral Envelope Proteins; Mitochondria; Amino Acid Substitution; Adult
PubMed: 38886481
DOI: 10.1038/s41598-024-64943-3 -
Trends in Molecular Medicine Jun 2024Herpes simplex virus type 1 (HSV-1) is a DNA virus and human pathogen used to construct promising therapeutic vectors. HSV-1 vectors fall into two classes:... (Review)
Review
Herpes simplex virus type 1 (HSV-1) is a DNA virus and human pathogen used to construct promising therapeutic vectors. HSV-1 vectors fall into two classes: replication-selective oncolytic vectors for cancer therapy and defective non-replicative vectors for gene therapy. Vectors from each class can accommodate ≥30 kb of inserts, have been approved clinically, and demonstrate a relatively benign safety profile. Despite oncolytic HSV (oHSV) replication in tumors and elicited immune responses, the virus is well tolerated in cancer patients. Current non-replicative vectors elicit only limited immune responses. Seropositivity and immune responses against HSV-1 do not eliminate either the vector or infected cells, and the vectors can therefore be re-administered. In this review we highlight vectors that have been translated to the clinic and host-virus immune interactions that impact on the safety and efficacy of HSVs.
PubMed: 38886138
DOI: 10.1016/j.molmed.2024.05.014 -
Virus Evolution 2024Influenza infections result in considerable public health and economic impacts each year. One of the contributing factors to the high annual incidence of human influenza...
Influenza infections result in considerable public health and economic impacts each year. One of the contributing factors to the high annual incidence of human influenza is the virus's ability to evade acquired immunity through continual antigenic evolution. Understanding the evolutionary forces that act within and between hosts is therefore critical to interpreting past trends in influenza virus evolution and in predicting future ones. Several studies have analyzed longitudinal patterns of influenza A virus genetic diversity in natural human infections to assess the relative contributions of selection and genetic drift on within-host evolution. However, in these natural infections, within-host viral populations harbor very few single-nucleotide variants, limiting our resolution in understanding the forces acting on these populations . Furthermore, low levels of within-host viral genetic diversity limit the ability to infer the extent of drift across transmission events. Here, we propose to use influenza virus genomic diversity as an alternative signal to better understand within- and between-host patterns of viral evolution. Specifically, we focus on the dynamics of defective viral genomes (DVGs), which harbor large internal deletions in one or more of influenza virus's eight gene segments. Our longitudinal analyses of DVGs show that influenza A virus populations are highly dynamic within hosts, corroborating previous findings based on viral genetic diversity that point toward the importance of genetic drift in driving within-host viral evolution. Furthermore, our analysis of DVG populations across transmission pairs indicates that DVGs rarely appeared to be shared, indicating the presence of tight transmission bottlenecks. Our analyses demonstrate that viral genomic diversity can be used to complement analyses based on viral genetic diversity to reveal processes that drive viral evolution within and between hosts.
PubMed: 38883977
DOI: 10.1093/ve/veae042 -
Journal of Virology Jun 2024The picornavirus genome encodes a large, single polyprotein that is processed by viral proteases to form an active replication complex. The replication complex is formed...
UNLABELLED
The picornavirus genome encodes a large, single polyprotein that is processed by viral proteases to form an active replication complex. The replication complex is formed with the viral genome, host proteins, and viral proteins that are produced/translated directly from each of the viral genomes (viral proteins provided in ). Efficient complementation of replication complex formation by viral proteins provided in , thus exogenous or ectopically expressed viral proteins, remains to be demonstrated. Here, we report an efficient complementation system for the replication of defective poliovirus (PV) mutants by a viral polyprotein precursor in HEK293 cells. Viral 3AB in the polyprotein, but not 2BC, was processed exclusively in . Replication of a defective PV replicon mutant, with a disrupted cleavage site for viral 3C protease between 3C and 3D (3C/D[A/G] mutant) could be rescued by a viral polyprotein provided in . Only a defect of 3D activity of the replicon could be rescued in ; inactivating mutations in 2C, 3B, and 3C of the replicon completely abrogated the -rescued replication. An intact N-terminus of the 3C domain of the 3CD provided in was essential for the -active function. By using this complementation system, a high-titer defective PV pseudovirus (PV) (>10 infectious units per mL) could be produced with the defective mutants, whose replication was completely dependent on complementation. This work reveals potential roles of exogenous viral proteins in PV replication and offers insights into protein/protein interaction during picornavirus infection.
IMPORTANCE
Viral polyprotein processing is an elaborately controlled step by viral proteases encoded in the polyprotein; fully processed proteins and processing intermediates need to be correctly produced for replication, which can be detrimentally affected even by a small modification of the polyprotein. Purified/isolated viral proteins can retain their enzymatic activities required for viral replication, such as protease, helicase, polymerase, etc. However, when these proteins of picornavirus are exogenously provided (provided in ) to the viral replication complex with a defective viral genome, replication is generally not rescued/complemented, suggesting the importance of viral proteins endogenously provided (provided in ) to the replication complex. In this study, I discovered that only the viral polymerase activity of poliovirus (PV) (the typical member of picornavirus family) could be efficiently rescued by exogenously expressed viral proteins. The current study reveals potential roles for exogenous viral proteins in viral replication and offers insights into interactions during picornavirus infection.
PubMed: 38837378
DOI: 10.1128/jvi.00523-24 -
Long-term trial of protection provided by adenovirus-vectored vaccine expressing the PPRV H protein.NPJ Vaccines Jun 2024A recombinant, replication-defective, adenovirus-vectored vaccine expressing the H surface glycoprotein of peste des petits ruminants virus (PPRV) has previously been...
A recombinant, replication-defective, adenovirus-vectored vaccine expressing the H surface glycoprotein of peste des petits ruminants virus (PPRV) has previously been shown to protect goats from challenge with wild-type PPRV at up to 4 months post vaccination. Here, we present the results of a longer-term trial of the protection provided by such a vaccine, challenging animals at 6, 9, 12 and 15 months post vaccination. Vaccinated animals developed high levels of anti-PPRV H protein antibodies, which were virus-neutralising, and the level of these antibodies was maintained for the duration of the trial. The vaccinated animals were largely protected against overt clinical disease from the challenge virus. Although viral genome was intermittently detected in blood samples, nasal and/or ocular swabs of vaccinated goats post challenge, viral RNA levels were significantly lower compared to unvaccinated control animals and vaccinated goats did not appear to excrete live virus. This protection, like the antibody response, was maintained at the same level for at least 15 months after vaccination. In addition, we showed that animals that have been vaccinated with the adenovirus-based vaccine can be revaccinated with the same vaccine after 12 months and showed an increased anti-PPRV antibody response after this boost vaccination. Such vaccines, which provide a DIVA capability, would therefore be suitable for use when the current live attenuated PPRV vaccines are withdrawn at the end of the ongoing global PPR eradication campaign.
PubMed: 38830899
DOI: 10.1038/s41541-024-00892-2 -
Research Square May 2024SARS-CoV-2 uses the double-membrane vesicles as replication organelles. However, how virion assembly occurs has not been fully understood. Here we identified a...
SARS-CoV-2 uses the double-membrane vesicles as replication organelles. However, how virion assembly occurs has not been fully understood. Here we identified a SARS-CoV-2-driven membrane structure named the 3a dense body (3DB). 3DBs have unusual electron-dense and dynamic inner structures, and their formation is driven by the accessory protein ORF3a via hijacking a specific subset of the -Golgi network (TGN) and early endosomal membranes. 3DB formation is conserved in related bat and pangolin coronaviruses yet lost during the evolution to SARS-CoV. 3DBs recruit the viral structural proteins spike (S) and membrane (M) and undergo dynamic fusion/fission to facilitate efficient virion assembly. A recombinant SARS-CoV-2 virus with an ORF3a mutant specifically defective in 3DB formation showed dramatically reduced infectivity for both extracellular and cell-associated virions. Our study uncovers the crucial role of 3DB in optimal SARS-CoV-2 infectivity and highlights its potential as a target for COVID-19 prophylactics and therapeutics.
PubMed: 38798602
DOI: 10.21203/rs.3.rs-4292014/v1 -
Viruses May 2024People with HIV exhibit persistent inflammation that correlates with HIV-associated comorbidities including accelerated aging, increased risk of cardiovascular disease,... (Review)
Review
People with HIV exhibit persistent inflammation that correlates with HIV-associated comorbidities including accelerated aging, increased risk of cardiovascular disease, and neuroinflammation. Mechanisms that perpetuate chronic inflammation in people with HIV undergoing antiretroviral treatments are poorly understood. One hypothesis is that the persistent low-level expression of HIV proviruses, including RNAs generated from defective proviral genomes, drives the immune dysfunction that is responsible for chronic HIV pathogenesis. We explore factors during HIV infection that contribute to the generation of a pool of defective proviruses as well as how HIV-1 mRNA and proteins alter immune function in people living with HIV.
Topics: Humans; HIV Infections; Inflammation; HIV-1; Transcription, Genetic; Proviruses; Protein Biosynthesis; RNA, Viral
PubMed: 38793632
DOI: 10.3390/v16050751 -
Viruses May 2024The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic... (Review)
Review
The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic cellular injuries. The immune system, encompassing both innate and adaptive immunity, therefore acts as a double-edged sword in viral infection. Insufficient potency permits pathogens to establish lifelong persistent infection and its consequences, while excessive activation leads to organ damage beyond its mission to control viral pathogens. The innate immune response serves as the front line of defense against viral infection, which is triggered through the recognition of viral products, referred to as pathogen-associated molecular patterns (PAMPs), by host cell pattern recognition receptors (PRRs). The PRRs-PAMPs interaction results in the induction of interferon-stimulated genes (ISGs) in infected cells, as well as the secretion of interferons (IFNs), to establish a tissue-wide antiviral state in an autocrine and paracrine manner. Cumulative evidence suggests significant variability in the expression patterns of PRRs, the induction potency of ISGs and IFNs, and the IFN response across different cell types and species. Hence, in our understanding of viral hepatitis pathogenesis, insights gained through hepatoma cell lines or murine-based experimental systems are uncertain in precisely recapitulating the innate antiviral response of genuine human hepatocytes. Accordingly, this review article aims to extract and summarize evidence made possible with bona fide human hepatocytes-based study tools, along with their clinical relevance and implications, as well as to identify the remaining gaps in knowledge for future investigations.
Topics: Humans; Hepatitis D; Hepatitis Delta Virus; Hepatocytes; Host-Pathogen Interactions; Immunity, Innate; Interferons; Pathogen-Associated Molecular Pattern Molecules; Receptors, Pattern Recognition
PubMed: 38793622
DOI: 10.3390/v16050740 -
Viruses Apr 2024Chronic Hepatitis B and D Virus (HBV and HDV) co-infection is responsible for the most severe form of viral Hepatitis, the Hepatitis Delta. Despite an efficient vaccine... (Review)
Review
Chronic Hepatitis B and D Virus (HBV and HDV) co-infection is responsible for the most severe form of viral Hepatitis, the Hepatitis Delta. Despite an efficient vaccine against HBV, the HBV/HDV infection remains a global health burden. Notably, no efficient curative treatment exists against any of these viruses. While physiologically distinct, HBV and HDV life cycles are closely linked. HDV is a deficient virus that relies on HBV to fulfil is viral cycle. As a result, the cellular response to HDV also influences HBV replication. In vitro studying of HBV and HDV infection and co-infection rely on various cell culture models that differ greatly in terms of biological relevance and amenability to classical virology experiments. Here, we review the various cell culture models available to scientists to decipher HBV and HDV virology and host-pathogen interactions. We discuss their relevance and how they may help address the remaining questions, with one objective in mind: the development of new therapeutic approaches allowing viral clearance in patients.
Topics: Humans; Hepatitis Delta Virus; Hepatitis B virus; Hepatitis D; Virus Replication; Animals; Host-Pathogen Interactions; Coinfection; Cell Culture Techniques; Hepatitis B
PubMed: 38793598
DOI: 10.3390/v16050716