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Microbiological Reviews Sep 1994The alphaviruses are a genus of 26 enveloped viruses that cause disease in humans and domestic animals. Mosquitoes or other hematophagous arthropods serve as vectors for... (Review)
Review
The alphaviruses are a genus of 26 enveloped viruses that cause disease in humans and domestic animals. Mosquitoes or other hematophagous arthropods serve as vectors for these viruses. The complete sequences of the +/- 11.7-kb plus-strand RNA genomes of eight alphaviruses have been determined, and partial sequences are known for several others; this has made possible evolutionary comparisons between different alphaviruses as well as comparisons of this group of viruses with other animal and plant viruses. Full-length cDNA clones from which infectious RNA can be recovered have been constructed for four alphaviruses; these clones have facilitated many molecular genetic studies as well as the development of these viruses as expression vectors. From these and studies involving biochemical approaches, many details of the replication cycle of the alphaviruses are known. The interactions of the viruses with host cells and host organisms have been exclusively studied, and the molecular basis of virulence and recovery from viral infection have been addressed in a large number of recent papers. The structure of the viruses has been determined to about 2.5 nm, making them the best-characterized enveloped virus to date. Because of the wealth of data that has appeared, these viruses represent a well-characterized system that tell us much about the evolution of RNA viruses, their replication, and their interactions with their hosts. This review summarizes our current knowledge of this group of viruses.
Topics: Alphavirus; Amino Acid Sequence; Base Sequence; Biological Evolution; Gene Expression Regulation, Viral; Models, Molecular; Molecular Sequence Data; Virus Replication
PubMed: 7968923
DOI: 10.1128/mr.58.3.491-562.1994 -
Nature Feb 2022Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history....
Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described, most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2-E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD-Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2-E1-mediated infection of human and mouse neurons in culture. The administration of a VLDLR LBD-Fc fusion protein has protective activity against rapidly fatal Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis.
Topics: Animals; LDL-Receptor Related Proteins; Ligands; Mice; Mosquito Vectors; Receptors, LDL; Semliki forest virus; Sindbis Virus
PubMed: 34929721
DOI: 10.1038/s41586-021-04326-0 -
Viruses Jun 2014Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for... (Review)
Review
Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. The most commonly used delivery vectors are based on three single-stranded encapsulated alphaviruses, namely Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. Alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-proficient particles. Moreover, in vitro transcribed RNA, as well as layered DNA vectors have been applied for immunization. A large number of highly immunogenic viral structural proteins expressed from alphavirus vectors have elicited strong neutralizing antibody responses in multispecies animal models. Furthermore, immunization studies have demonstrated robust protection against challenges with lethal doses of virus in rodents and primates. Similarly, vaccination with alphavirus vectors expressing tumor antigens resulted in prophylactic protection against challenges with tumor-inducing cancerous cells. As certain alphaviruses, such as Chikungunya virus, have been associated with epidemics in animals and humans, attention has also been paid to the development of vaccines against alphaviruses themselves. Recent progress in alphavirus vector development and vaccine technology has allowed conducting clinical trials in humans.
Topics: Alphavirus; Alphavirus Infections; Animals; Cancer Vaccines; Clinical Trials as Topic; Genetic Vectors; Humans; Vaccines, DNA; Viral Vaccines
PubMed: 24937089
DOI: 10.3390/v6062392 -
Viruses Mar 2018Alphavirus nucleocapsids are assembled in the cytoplasm of infected cells from 240 copies of the capsid protein and the approximately 11 kb positive strand genomic RNA.... (Review)
Review
Alphavirus nucleocapsids are assembled in the cytoplasm of infected cells from 240 copies of the capsid protein and the approximately 11 kb positive strand genomic RNA. However, the challenge of how the capsid specifically selects its RNA package and assembles around it has remained an elusive one to solve. In this review, we will summarize what is known about the alphavirus capsid protein, the packaging signal, and their roles in the mechanism of packaging and assembly. We will review the discovery of the packaging signal and how there is as much evidence for, as well as against, its requirement to specify packaging of the genomic RNA. Finally, we will compare this model with those of other viral systems including particular reference to a relatively new idea of RNA packaging based on the presence of multiple minimal packaging signals throughout the genome known as the two stage mechanism. This review will provide a basis for further investigating the fundamental ways of how RNA viruses are able to select their own cargo from the relative chaos that is the cytoplasm.
Topics: Alphavirus; Animals; Capsid Proteins; Humans; Models, Biological; Nucleocapsid; Virus Assembly; Virus Replication
PubMed: 29558394
DOI: 10.3390/v10030138 -
Nature Reviews. Microbiology Jun 2023Alphaviruses are arthropod-transmitted RNA viruses that cause epidemics of human infection and disease on a global scale. These viruses are classified as either... (Review)
Review
Alphaviruses are arthropod-transmitted RNA viruses that cause epidemics of human infection and disease on a global scale. These viruses are classified as either arthritogenic or encephalitic based on their genetic relatedness and the clinical syndromes they cause. Although there are currently no approved therapeutics or vaccines against alphaviruses, passive transfer of monoclonal antibodies confers protection in animal models. This Review highlights recent advances in our understanding of the host factors required for alphavirus entry, the mechanisms of action by which protective antibodies inhibit different steps in the alphavirus infection cycle and candidate alphavirus vaccines currently under clinical evaluation that focus on humoral immunity. A comprehensive understanding of alphavirus entry and antibody-mediated protection may inform the development of new classes of countermeasures for these emerging viruses.
Topics: Animals; Humans; Alphavirus; Alphavirus Infections; Antibodies, Monoclonal
PubMed: 36474012
DOI: 10.1038/s41579-022-00825-7 -
Journal of Virology Sep 2021Alphaviruses have positive-strand RNA genomes containing two open reading frames (ORFs). The first ORF encodes the nonstructural (ns) polyproteins P123 and P1234 that...
Alphaviruses have positive-strand RNA genomes containing two open reading frames (ORFs). The first ORF encodes the nonstructural (ns) polyproteins P123 and P1234 that act as precursors for the subunits of the viral RNA replicase (nsP1 to nsP4). Processing of P1234 leads to the formation of a negative-strand replicase consisting of nsP4 (RNA polymerase) and P123 components. Subsequent processing of P123 results in a positive-strand replicase. The second ORF encoding the structural proteins is expressed via the synthesis of a subgenomic RNA. Alphavirus replicase is capable of using template RNAs that contain essential -active sequences. Here, we demonstrate that the replicases of nine alphaviruses, expressed in the form of separate P123 and nsP4 components, are active. Their activity depends on the abundance of nsP4. The match of nsP4 to its template strongly influences efficient subgenomic RNA synthesis. nsP4 of Barmah Forest virus (BFV) formed a functional replicase only with matching P123, while nsP4s of other alphaviruses were compatible also with several heterologous P123s. The P123 components of Venezuelan equine encephalitis virus and Sindbis virus (SINV) required matching nsP4s, while P123 of other viruses could form active replicases with different nsP4s. Chimeras of Semliki Forest virus, harboring the nsP4 of chikungunya virus, Ross River virus, BFV, or SINV were viable. In contrast, chimeras of SINV, harboring an nsP4 from different alphaviruses, exhibited a temperature-sensitive phenotype. These findings highlight the possibility for formation of new alphaviruses via recombination events and provide a novel approach for the development of attenuated chimeric viruses for vaccination strategies. A key element of every virus with an RNA genome is the RNA replicase. Understanding the principles of RNA replicase formation and functioning is therefore crucial for understanding and responding to the emergence of new viruses. Reconstruction of the replicases of nine alphaviruses from nsP4 and P123 polyproteins revealed that the nsP4 of the majority of alphaviruses, including the mosquito-specific Eilat virus, could form a functional replicase with P123 originating from a different virus, and the corresponding chimeric viruses were replication-competent. nsP4 also had an evident role in determining the template RNA preference and the efficiency of RNA synthesis. The revealed broad picture of the compatibility of the replicase components of alphaviruses is important for understanding the formation and functioning of the alphavirus RNA replicase and highlights the possibilities for recombination between different alphavirus species.
Topics: Alphavirus; Alphavirus Infections; Animals; Base Sequence; Cell Line; DNA-Directed RNA Polymerases; Humans; Polyproteins; RNA, Viral; RNA-Dependent RNA Polymerase; Viral Nonstructural Proteins; Viral Replicase Complex Proteins; Virus Replication
PubMed: 34319783
DOI: 10.1128/JVI.00355-21 -
Viruses May 2015Alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range... (Review)
Review
Alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range of mammalian host cell transduction. Mainly three types of alphavirus vectors, namely naked RNA, recombinant particles and DNA/RNA layered vectors, have been subjected to preclinical studies with the goal of achieving prophylactic or therapeutic efficacy, particularly in oncology. In this context, immunization with alphavirus vectors has provided protection against challenges with tumor cells. Moreover, alphavirus intratumoral and systemic delivery has demonstrated substantial tumor regression and significant prolonged survival rates in various animal tumor models. Recent discoveries of the strong association of RNA interference and disease have accelerated gene therapy based approaches, where alphavirus-based gene delivery can play an important role.
Topics: Alphavirus; Cancer Vaccines; Drug Carriers; Genetic Therapy; Humans; Neoplasms; Transduction, Genetic
PubMed: 25961488
DOI: 10.3390/v7052321 -
Current Opinion in Virology Feb 2018Alphaviruses are important human pathogens that cause diseases ranging from acute and chronic polyarthralgia to encephalitis. Transmitted by mosquito vectors,... (Review)
Review
Alphaviruses are important human pathogens that cause diseases ranging from acute and chronic polyarthralgia to encephalitis. Transmitted by mosquito vectors, alphaviruses have high potential for emergence and have initiated several recent epidemics. The innate immune response is critical for controlling the acute phase of alphavirus disease, and the induction of type I interferon (IFN) is essential in this response. In this review, we discuss our current understanding of innate host sensors that initiate antiviral responses following alphavirus infection, and the IFN-induced effector proteins that limit alphavirus replication and dissemination.
Topics: Alphavirus; Alphavirus Infections; Animals; Humans; Immunity, Innate; Interferon Type I; Mice; Toll-Like Receptors; Virus Replication
PubMed: 29175515
DOI: 10.1016/j.coviro.2017.11.006 -
Advances in Virus Research 2020Alphaviruses, members of the enveloped, positive-sense, single-stranded RNA Togaviridae family, represent a reemerging public health threat as mosquito vectors expand...
Alphaviruses, members of the enveloped, positive-sense, single-stranded RNA Togaviridae family, represent a reemerging public health threat as mosquito vectors expand into new geographic territories. The Old World alphaviruses, which include chikungunya virus, Ross River virus, and Sindbis virus, tend to cause a clinical syndrome characterized by fever, rash, and arthritis, whereas the New World alphaviruses, which consist of Venezuelan equine encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus, induce encephalomyelitis. Following recovery from the acute phase of infection, many patients are left with debilitating persistent joint and neurological complications that can last for years. Clues from human cases and studies using animal models strongly suggest that much of the disease and pathology induced by alphavirus infection, particularly atypical and chronic manifestations, is mediated by the immune system rather than directly by the virus. This review discusses the current understanding of the immunopathogenesis of the arthritogenic and neurotropic alphaviruses accumulated through both natural infection of humans and experimental infection of animals, particularly mice. As treatment following alphavirus infection is currently limited to supportive care, understanding the contribution of the immune system to the disease process is critical to developing safe and effective therapies.
Topics: Alphavirus; Alphavirus Infections; Animals; Encephalitis Virus, Venezuelan Equine; Horses; Humans; Mice
PubMed: 32711733
DOI: 10.1016/bs.aivir.2020.06.002 -
PLoS Pathogens Oct 2020Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection,... (Review)
Review
Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection, intensive research efforts have focused on elucidating aspects of this pathway, including attachment, internalization, and fusion. Herein, we review recent developments in the molecular understanding of alphavirus entry both in vitro and in vivo and how these advances might enable the design of therapeutics targeting this critical step in the alphavirus life cycle.
Topics: Alphavirus; Alphavirus Infections; Animals; Host-Pathogen Interactions; Humans; Virus Internalization; Virus Replication
PubMed: 33091085
DOI: 10.1371/journal.ppat.1008876