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Viruses Jan 2022Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of... (Review)
Review
Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.
Topics: Antiviral Agents; Capsid Proteins; Humans; RNA Virus Infections; RNA Viruses; Virus Assembly; Virus Replication
PubMed: 35215767
DOI: 10.3390/v14020174 -
Viruses Nov 2018The mechanisms that drive formation of the HIV capsid, first as an immature particle and then as a mature protein shell, remain incompletely understood. Recent... (Review)
Review
The mechanisms that drive formation of the HIV capsid, first as an immature particle and then as a mature protein shell, remain incompletely understood. Recent discoveries of positively-charged rings in the immature and mature protein hexamer subunits that comprise them and their binding to the cellular metabolite inositol hexakisphosphate (IP6) have stimulated exciting new hypotheses. In this paper, we discuss how data from multiple structural and biochemical approaches are revealing potential roles for IP6 in the HIV-1 replication cycle from assembly to uncoating.
Topics: Capsid; HIV-1; Phytic Acid; Virus Assembly; Virus Uncoating
PubMed: 30445742
DOI: 10.3390/v10110640 -
Journal of Virology May 2019Tailed double-stranded DNA (dsDNA) bacteriophages, herpesviruses, and adenoviruses package their genetic material into a precursor capsid through a dodecameric ring...
Tailed double-stranded DNA (dsDNA) bacteriophages, herpesviruses, and adenoviruses package their genetic material into a precursor capsid through a dodecameric ring complex called the portal protein, which is located at a unique 5-fold vertex. In several phages and viruses, including T4, Φ29, and herpes simplex virus 1 (HSV-1), the portal forms a nucleation complex with scaffolding proteins (SPs) to initiate procapsid (PC) assembly, thereby ensuring incorporation of only one portal ring per capsid. However, for bacteriophage P22, the role of its portal protein in initiation of procapsid assembly is unclear. We have developed an P22 assembly assay where portal protein is coassembled into procapsid-like particles (PLPs). Scaffolding protein also catalyzes oligomerization of monomeric portal protein into dodecameric rings, possibly forming a scaffolding protein-portal protein nucleation complex that results in one portal ring per P22 procapsid. Here, we present evidence substantiating that the P22 portal protein, similarly to those of other dsDNA viruses, can act as an assembly nucleator. The presence of the P22 portal protein is shown to increase the rate of particle assembly and contribute to proper morphology of the assembled particles. Our results highlight a key function of portal protein as an assembly initiator, a feature that is likely conserved among these classes of dsDNA viruses. The existence of a single portal ring is essential to the formation of infectious virions in the tailed double-stranded DNA (dsDNA) phages, herpesviruses, and adenoviruses and, as such, is a viable antiviral therapeutic target. How only one portal is selectively incorporated at a unique vertex is unclear. In many dsDNA viruses and phages, the portal protein acts as an assembly nucleator. However, early work on phage P22 assembly indicated that the portal protein did not function as a nucleator for procapsid (PC) assembly, leading to the suggestion that P22 uses a unique mechanism for portal incorporation. Here, we show that portal protein nucleates assembly of P22 procapsid-like particles (PLPs). Addition of portal rings to an assembly reaction increases the rate of formation and yield of particles and corrects improper particle morphology. Our data suggest that procapsid assembly may universally initiate with a nucleation complex composed minimally of portal and scaffolding proteins (SPs).
Topics: Bacteriophage P22; Capsid; Virus Assembly
PubMed: 30787152
DOI: 10.1128/JVI.00187-19 -
The Journal of Biological Chemistry Apr 2019The lifecycle of retroviruses and retrotransposons includes a reverse transcription step, wherein dsDNA is synthesized from genomic RNA for subsequent insertion into the... (Review)
Review
The lifecycle of retroviruses and retrotransposons includes a reverse transcription step, wherein dsDNA is synthesized from genomic RNA for subsequent insertion into the host genome. Retroviruses and retrotransposons commonly appropriate major components of the host cell translational machinery, including cellular tRNAs, which are exploited as reverse transcription primers. Nonpriming functions of tRNAs have also been proposed, such as in HIV-1 virion assembly, and tRNA-derived fragments may also be involved in retrovirus and retrotransposon replication. Moreover, host cellular proteins regulate retroviral replication by binding to tRNAs and thereby affecting various steps in the viral lifecycle. For example, in some cases, tRNA primer selection is facilitated by cognate aminoacyl-tRNA synthetases (ARSs), which bind tRNAs and ligate them to their corresponding amino acids, but also have many known nontranslational functions. Multi-omic studies have revealed that ARSs interact with both viral proteins and RNAs and potentially regulate retroviral replication. Here, we review the currently known roles of tRNAs and their derivatives in retroviral and retrotransposon replication and shed light on the roles of tRNA-binding proteins such as ARSs in this process.
Topics: Amino Acyl-tRNA Synthetases; Animals; HIV Infections; HIV-1; Humans; RNA, Transfer; Virus Assembly
PubMed: 30700559
DOI: 10.1074/jbc.REV118.002957 -
BioMed Research International 2023The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which... (Review)
Review
The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer-the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.
Topics: Humans; Hepacivirus; Lipid Droplets; Virus Replication; Persistent Infection; Hepatitis C; Virus Assembly; Lipid Metabolism
PubMed: 37090186
DOI: 10.1155/2023/5156601 -
Virologie (Montrouge, France) Feb 2019
Topics: Biomedical Research; CRISPR-Cas Systems; Drug Delivery Systems; Gene Editing; Gene Transfer Techniques; Genetic Vectors; Humans; Nanotechnology; Virion; Virus Assembly
PubMed: 31131829
DOI: 10.1684/vir.2019.0759 -
Virology Aug 2018HIV-1 Maturation inhibitors (MIs) bind to the C-terminal domain of capsid protein (CA-CTD) and spacer peptide 1 (SP1) in HIV-1 Gag and inhibit the CA-SP1 cleavage by...
HIV-1 Maturation inhibitors (MIs) bind to the C-terminal domain of capsid protein (CA-CTD) and spacer peptide 1 (SP1) in HIV-1 Gag and inhibit the CA-SP1 cleavage by stabilizing the immature Gag. The β-turn motif, GVGGP in the HIV CA-CTD (residues 220-224) is one of the key determinants of HIV Gag assembly. In the present study, we mutated each residue of HIV-1 β-turn motif to alanine and observed complete inhibition of virus release of all mutants. This defect in virus release was rescued in the presence of maturation inhibitors; BVM and PF-46396 for P224A mutant. To our knowledge, this is the first report of identification of BVM and PF-46396-dependent capsid mutant. Our results highlight the importance of the core β-turn motif residues in immature virus assembly and suggest that the presence of MIs enhances Gag membrane binding and multimerization thereby restoring virus release of HIV Gag P224 mutant.
Topics: Amino Acid Motifs; Anti-HIV Agents; Capsid Proteins; Cell Line; Genes, gag; HIV-1; Humans; Mutation; T-Lymphocytes; Virus Assembly; gag Gene Products, Human Immunodeficiency Virus
PubMed: 29879541
DOI: 10.1016/j.virol.2018.05.024 -
Current Opinion in Virology Dec 2020Alphaviruses are transmitted by an arthropod vector to a vertebrate host. The disease pathologies, cellular environments, immune responses, and host factors are very... (Review)
Review
Alphaviruses are transmitted by an arthropod vector to a vertebrate host. The disease pathologies, cellular environments, immune responses, and host factors are very different in these organisms. Yet, the virus is able to infect, replicate, and assemble into new particles in these two animals using one set of genetic instructions. The balance between conserved mechanisms and unique strategies during virus assembly is critical for fitness of the virus. In this review, we discuss new findings in receptor binding, polyprotein topology, nucleocapsid core formation, and particle budding that have emerged in the last five years and share opinions on how these new findings might answer some questions regarding alphavirus structure and assembly.
Topics: Alphavirus; Animals; Arthropods; Protein Binding; Viral Envelope Proteins; Virus Assembly; Virus Release
PubMed: 32683295
DOI: 10.1016/j.coviro.2020.06.005 -
Virology Nov 2019We present a novel kinetic Monte Carlo model to simulate the real process time-scale of the assembly of Human Papillomavirus (HPV) virus-like particles (VLPs)...
We present a novel kinetic Monte Carlo model to simulate the real process time-scale of the assembly of Human Papillomavirus (HPV) virus-like particles (VLPs) incorporating the formation of intercapsomeric disulfide bonds. The objective was to develop insights into the underlying mechanisms of HPV VLP assembly and cross-linking during in vitro production of the HPV vaccine. The model integrates actual experimental data and detailed information of VLP geometrical structure in microscopic mechanistic steps. The principal novelty of this model is in the concurrent simulation of VLP assembly and cross-linking including a variable for spatial angular arrangement of capsomeres during their assembly that affects the overall rates of VLP assembly and cross-linking. The cross-linking modeled by using the mechanistic probability rules between involved cysteine residues. The model was utilized to better understand the actual process data and check on the hypothesis related to factors affecting the rates of HPV growth and maturation.
Topics: Humans; Models, Biological; Papillomaviridae; Protein Multimerization; Time Factors; Viral Proteins; Virosomes; Virus Assembly
PubMed: 31450047
DOI: 10.1016/j.virol.2019.08.018 -
Viruses Jun 2016Influenza A viruses (IAVs) harbor a segmented RNA genome that is organized into eight distinct viral ribonucleoprotein (vRNP) complexes. Although a segmented genome may... (Review)
Review
Influenza A viruses (IAVs) harbor a segmented RNA genome that is organized into eight distinct viral ribonucleoprotein (vRNP) complexes. Although a segmented genome may be a major advantage to adapt to new host environments, it comes at the cost of a highly sophisticated genome packaging mechanism. Newly synthesized vRNPs conquer the cellular endosomal recycling machinery to access the viral budding site at the plasma membrane. Genome packaging sequences unique to each RNA genome segment are thought to be key determinants ensuring the assembly and incorporation of eight distinct vRNPs into progeny viral particles. Recent studies using advanced fluorescence microscopy techniques suggest the formation of vRNP sub-bundles (comprising less than eight vRNPs) during their transport on recycling endosomes. The formation of such sub-bundles might be required for efficient packaging of a bundle of eight different genomes segments at the budding site, further highlighting the complexity of IAV genome packaging.
Topics: Influenza A virus; Ribonucleoproteins; Virus Assembly
PubMed: 27322310
DOI: 10.3390/v8060165