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Frontiers in Immunology 2023Viral-based cancer therapies have tremendous potential, especially in the context of treating poorly infiltrated cold tumors. However, in tumors with intact anti-viral... (Review)
Review
Viral-based cancer therapies have tremendous potential, especially in the context of treating poorly infiltrated cold tumors. However, in tumors with intact anti-viral interferon (IFN) pathways, while some oncolytic viruses induce strong innate and adaptive immune responses, they are neutralized before exerting their therapeutic effect. Arenaviruses, particularly the lymphocytic choriomeningitis virus (LCMV) is a noncytopathic virus with preferential cancer tropism and evolutionary mechanisms to escape the immune system for longer and to block early clearance. These escape mechanisms include inhibition of the MAVS dependent IFN pathway and spike protein antigen masking. Regarding its potential for cancer treatment, LCMV is therefore able to elicit long-term responses within the tumor microenvironment (TME), boost anti-tumor immune responses and polarize poorly infiltrating tumors towards a hot phenotype. Other arenaviruses including the attenuated Junin virus vaccine also have anti-tumor effects. Furthermore, the LCMV and Pichinde arenaviruses are currently being used to create vector-based vaccines with attenuated but replicating virus. This review focuses on highlighting the potential of arenaviruses as anti-cancer therapies. This includes providing a molecular understanding of its tropism as well as highlighting past and present preclinical and clinical applications of noncytophatic arenavirus therapies and their potential in bridging the gap in the treatment of cancers weakly responsive or unresponsive to oncolytic viruses. In summary, arenaviruses represent promising new therapies to broaden the arsenal of anti-tumor therapies for generating an immunogenic tumor microenvironment.
Topics: Lymphocytic choriomeningitis virus; Interferons; Neoplasms
PubMed: 37033933
DOI: 10.3389/fimmu.2023.1110522 -
Acta Virologica Mar 2016Lymphocytic choriomeningitis virus (LCMV) is a prototype virus of the Arenaviridae family that is attracting considerable attention both as an important experimental... (Review)
Review
Lymphocytic choriomeningitis virus (LCMV) is a prototype virus of the Arenaviridae family that is attracting considerable attention both as an important experimental model system to study acute and persistent viral infections, and as a neglected human pathogen of clinical significance. Notably, LCMV is capable of persisting in an infected host, and escaping the immune system. Here we describe the strategies used by the virus to establish and maintain long-term infection in vitro and/or persistent infection in vivo. We discuss how the viral components (RNA, nucleoprotein, glycoprotein, Z protein) manipulate the host cell machinery to facilitate survival and spread of the virus without disturbing the basal cellular processes. Deep understanding of these strategies is inevitable for the development of approaches towards restricting the virus spread and/or preventing its harmful reactivation. This review summarizes the current status in this area and presents ideas emerging from existing data.
Topics: Animals; Humans; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus
PubMed: 26982463
DOI: 10.4149/av_2016_01_15 -
Optimal reference genes for RNA tissue analysis in small animal models of hemorrhagic fever viruses.Scientific Reports Nov 2023Reverse-transcription quantitative polymerase chain reaction assays are frequently used to evaluate gene expression in animal model studies. Data analyses depend on...
Reverse-transcription quantitative polymerase chain reaction assays are frequently used to evaluate gene expression in animal model studies. Data analyses depend on normalization using a suitable reference gene (RG) to minimize effects of variation due to sample collection, sample processing, or experimental set-up. Here, we investigated the suitability of nine potential RGs in laboratory animals commonly used to study viral hemorrhagic fever infection. Using tissues (liver, spleen, gonad [ovary or testis], kidney, heart, lung, eye, brain, and blood) collected from naïve animals and those infected with Crimean-Congo hemorrhagic fever (mice), Nipah (hamsters), or Lassa (guinea pigs) viruses, optimal species-specific RGs were identified based on five web-based algorithms to assess RG stability. Notably, the Ppia RG demonstrated stability across all rodent tissues tested. Optimal RG pairs that include Ppia were determined for each rodent species (Ppia and Gusb for mice; Ppia and Hrpt for hamsters; and Ppia and Gapdh for guinea pigs). These RG pair assays were multiplexed with viral targets to improve assay turnaround time and economize sample usage. Finally, a pan-rodent Ppia assay capable of detecting Ppia across multiple rodent species was developed and successfully used in ecological investigations of field-caught rodents, further supporting its pan-species utility.
Topics: Cricetinae; Female; Male; Guinea Pigs; Animals; Mice; Hemorrhagic Fever Virus, Crimean-Congo; Dengue Virus; Models, Animal; Arenaviruses, New World; Cyclophilin A; RNA
PubMed: 37938597
DOI: 10.1038/s41598-023-45740-w -
EcoHealth Mar 2022In the Americas, infectious viral diseases caused by viruses of the genus Mammarenavirus have been reported since the 1960s. Such diseases have commonly been associated... (Review)
Review
In the Americas, infectious viral diseases caused by viruses of the genus Mammarenavirus have been reported since the 1960s. Such diseases have commonly been associated with land use changes, which favor abundance of generalist rodent species. In the Americas-where the rates of land use change are among the highest worldwide-at least 1326 of all 2277 known rodent species have been reported. We conducted a literature review of studies between 1960 and 2020, to establish the current and historical knowledge about genotypes of mammarenaviruses and their rodent reservoirs in the Americas. Our overall goal was to show the importance of focusing research efforts on the American continent, since the conditions exist for future viral hemorrhagic fever (VHF) outbreaks caused by rodent-borne viruses, in turn, carried by widely distributed rodents. We found 47 species identified down to the species level, and one species identified only down to the genus level (Oryzomys sp.), reported in the Americas as reservoirs of mammarenaviruses, most these are ecological generalists. These species associate with 29 genotypes of Mammarenavirus, seven of which have been linked to VHFs in humans. We also highlight the need to monitor these species, in order to prevent viral disease outbreaks in the region.
Topics: Americas; Animals; Arenaviridae; Disease Reservoirs; Hemorrhagic Fevers, Viral; Rodentia
PubMed: 35247117
DOI: 10.1007/s10393-022-01580-0 -
Nature Mar 2020Arenaviruses can cause severe haemorrhagic fever and neurological diseases in humans and other animals, exemplified by Lassa mammarenavirus, Machupo mammarenavirus and... (Comparative Study)
Comparative Study
Arenaviruses can cause severe haemorrhagic fever and neurological diseases in humans and other animals, exemplified by Lassa mammarenavirus, Machupo mammarenavirus and lymphocytic choriomeningitis virus, posing great threats to public health. These viruses encode a large multi-domain RNA-dependent RNA polymerase for transcription and replication of the viral genome. Viral polymerases are one of the leading antiviral therapeutic targets. However, the structure of arenavirus polymerase is not yet known. Here we report the near-atomic resolution structures of Lassa and Machupo virus polymerases in both apo and promoter-bound forms. These structures display a similar overall architecture to influenza virus and bunyavirus polymerases but possess unique local features, including an arenavirus-specific insertion domain that regulates the polymerase activity. Notably, the ordered active site of arenavirus polymerase is inherently switched on, without the requirement for allosteric activation by 5'-viral RNA, which is a necessity for both influenza virus and bunyavirus polymerases. Moreover, dimerization could facilitate the polymerase activity. These findings advance our understanding of the mechanism of arenavirus replication and provide an important basis for developing antiviral therapeutics.
Topics: Apoenzymes; Arenaviruses, New World; Catalytic Domain; Cryoelectron Microscopy; Lassa virus; Lymphocytic choriomeningitis virus; Models, Molecular; Promoter Regions, Genetic; RNA-Dependent RNA Polymerase; Virus Replication
PubMed: 32214249
DOI: 10.1038/s41586-020-2114-2 -
Current Opinion in Structural Biology Apr 2023Viruses are obligatory parasites that can replicate only inside host cells. Therefore, the evolutionary drive to enter cells is immense, leading to diversification in... (Review)
Review
Viruses are obligatory parasites that can replicate only inside host cells. Therefore, the evolutionary drive to enter cells is immense, leading to diversification in the cell-entry strategies of viruses. One of the most critical steps for cell entry is the recognition of the target cell, a process driven by the formation of viral/host macromolecular complexes. The accumulation of recent structural data for viruses within the arenaviridae family allows us to examine how different viral species from the same viral family utilize evolutionarily-related viral glycoproteins to engage with a variety of different cellular receptors. These structural data, compared to other viruses from the coronaviridae family, hint about possible routes that such viruses use for evolving new receptor-binding capabilities, allowing them to switch from one receptor to another.
Topics: Arenaviridae; Viruses; Receptors, Cell Surface; Protein Binding; Macromolecular Substances
PubMed: 36857816
DOI: 10.1016/j.sbi.2023.102561 -
Virulence Dec 2021Lassa fever (LF) is a deadly viral hemorrhagic disease that is endemic to West Africa. The causative agent of LF is Lassa virus (LASV), which causes approximately... (Review)
Review
Lassa fever (LF) is a deadly viral hemorrhagic disease that is endemic to West Africa. The causative agent of LF is Lassa virus (LASV), which causes approximately 300,000 infections and 5,000 deaths annually. There are currently no approved therapeutics or FDA-approved vaccines against LASV. The high genetic variability between LASV strains and immune evasion mediated by the virus complicate the development of effective therapeutics and vaccines. Here, we aim to provide a comprehensive review of the basic biology of LASV and its mechanisms of disease pathogenesis and virulence in various animal models, as well as an update on prospective vaccines, therapeutics, and diagnostics for LF. Until effective vaccines and/or therapeutics are available for use to prevent or treat LF, a better level of understanding of the basic biology of LASV, its natural genetic variations and immune evasion mechanisms as potential pathogenicity factors, and of the rodent reservoir-vector populations and their geographical distributions, is necessary for the development of accurate diagnostics and effective therapeutics and vaccines against this deadly human viral pathogen.
Topics: Animals; Immune Evasion; Lassa Fever; Lassa virus; Viral Vaccines; Virulence
PubMed: 34747339
DOI: 10.1080/21505594.2021.2000290 -
Viruses May 2021Rodents are a speciose group of mammals with strong zoonotic potential. Some parts of Africa are still underexplored for the occurrence of rodent-borne pathogens,...
Rodents are a speciose group of mammals with strong zoonotic potential. Some parts of Africa are still underexplored for the occurrence of rodent-borne pathogens, despite this high potential. Angola is at the convergence of three major biogeographical regions of sub-Saharan Africa, each harbouring a specific rodent community. This rodent-rich area is, therefore, strategic for studying the diversity and evolution of rodent-borne viruses. In this study we examined 290 small mammals, almost all rodents, for the presence of mammarenavirus and hantavirus RNA. While no hantavirus was detected, we found three rodent species positive for distinct mammarenaviruses with a particularly high prevalence in Namaqua rock rats (). We characterised four complete virus genomes, which showed typical mammarenavirus organisation. Phylogenetic and genetic distance analyses revealed: (i) the presence of a significantly divergent strain of Luna virus in Angolan representatives of the ubiquitous Natal multimammate mouse (), (ii) a novel Okahandja-related virus associated with the Angolan lineage of for which we propose the name Bitu virus (BITV) and (iii) the occurrence of a novel Mobala-like mammarenavirus in the grey-bellied pygmy mouse () for which we propose the name Kwanza virus (KWAV). This high virus diversity in a limited host sample size and in a relatively small geographical area supports the idea that Angola is a hotspot for mammarenavirus diversity.
Topics: Animals; Arenaviridae; Arenaviridae Infections; Disease Reservoirs; Genome, Viral; Geography, Medical; Phylogeny; Prevalence; RNA, Viral; Whole Genome Sequencing
PubMed: 34070551
DOI: 10.3390/v13060982 -
Emerging Infectious Diseases Mar 2023Lymphocytic choriomeningitis mammarenavirus (LCMV) is a globally distributed zoonotic pathogen transmitted by house mice (Mus musculus). We report the reemergence of...
Lymphocytic choriomeningitis mammarenavirus (LCMV) is a globally distributed zoonotic pathogen transmitted by house mice (Mus musculus). We report the reemergence of LCMV (lineages I and II) in wild house mice (Mus musculus domesticus) and LCMV lineage I in a diseased golden lion tamarin (Leontopithecus rosalia) from a zoo in Germany.
Topics: Animals; Mice; Lymphocytic choriomeningitis virus; Lymphocytic Choriomeningitis; Rodent Diseases; Germany
PubMed: 36823667
DOI: 10.3201/eid2903.221822 -
Methods in Molecular Biology (Clifton,... 2024Several mammarenaviruses cause hemorrhagic fever (HF) disease in humans and pose a significant public health problem in their endemic regions. The Old World (OW)...
Several mammarenaviruses cause hemorrhagic fever (HF) disease in humans and pose a significant public health problem in their endemic regions. The Old World (OW) mammarenavirus Lassa virus (LASV) is estimated to infect several hundred thousand people yearly in West Africa, resulting in high numbers of Lassa fever (LF) cases, a disease associated with high morbidity and mortality. No licensed vaccines are available to combat LASV infection, and anti-LASV drug therapy is limited to the off-label use of ribavirin whose efficacy remains controversial. The development of reverse genetics approaches has provided investigators with a powerful approach for the investigation of the molecular, cell biology and pathogenesis of mammarenaviruses. The use of cell-based minigenome systems has allowed examining the cis- and trans-acting factors involved in viral genome replication and gene transcription, assembly, and budding, which has facilitated the identification of several anti-mammarenavirus candidate drugs. Likewise, it is possible now to rescue infectious recombinant mammarenaviruses from cloned cDNAs containing predetermined mutations in their genomes to investigate virus-host interactions and mechanisms of viral pathogenesis. Reverse genetics have also allowed the generation of mammarenaviruses expressing foreign genes to facilitate virus detection, to identify antiviral drugs, and to generate live-attenuated vaccine (LAV) candidates. Likewise, reverse genetics techniques have allowed the generation of single-cycle infectious, reporter-expressing mammarenaviruses to study some aspects of the biology of HF-causing human mammarenavirus without the need of high security biocontainment laboratories. In this chapter, we describe the experimental procedures to generate recombinant (r)LASV using state-of-the-art plasmid-based reverse genetics.
Topics: Humans; Lassa virus; Reverse Genetics; Arenaviridae; Lassa Fever; Hemorrhagic Fevers, Viral; Plasmids
PubMed: 38064030
DOI: 10.1007/978-1-0716-3533-9_8