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1
Ren, Wenlin, Yunkai Zhu, Yuyan Wang, et al. "Comparative analysis reveals the species-specific genetic determinants of ACE2 required for SARS-CoV-2 entry." PLOS Pathogens 17, no. 3 (2021): e1009392. http://dx.doi.org/10.1371/journal.ppat.1009392.
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Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. Our study shed more lights into the genetic determinants of ACE2 as the functional receptor of SARS-CoV-2, which facilitates our understanding of viral entry.
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Peacock, Thomas P., Carol M. Sheppard, Ecco Staller, and Wendy S. Barclay. "Host Determinants of Influenza RNA Synthesis." Annual Review of Virology 6, no. 1 (2019): 215–33. http://dx.doi.org/10.1146/annurev-virology-092917-043339.
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Influenza viruses are a leading cause of seasonal and pandemic respiratory illness. Influenza is a negative-sense single-stranded RNA virus that encodes its own RNA-dependent RNA polymerase (RdRp) for nucleic acid synthesis. The RdRp catalyzes mRNA synthesis, as well as replication of the virus genome (viral RNA) through a complementary RNA intermediate. Virus propagation requires the generation of these RNA species in a controlled manner while competing heavily with the host cell for resources. Influenza virus appropriates host factors to enhance and regulate RdRp activity at every step of RNA synthesis. This review describes such host factors and summarizes our current understanding of the roles they play in viral synthesis of RNA.
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Hamid, Faysal Bin, Jinsun Kim, and Cha-Gyun Shin. "Cellular and viral determinants of retroviral nuclear entry." Canadian Journal of Microbiology 62, no. 1 (2016): 1–15. http://dx.doi.org/10.1139/cjm-2015-0350.
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Retroviruses must integrate their cDNA into the host genome to generate proviruses. Viral DNA–protein complexes interact with cellular proteins and produce pre-integration complexes, which carry the viral genome and cross the nuclear pore channel to enter the nucleus and integrate viral DNA into host chromosomal DNA. If the reverse transcripts fail to integrate, linear or circular DNA species such as 1- and 2-long terminal repeats are generated. Such complexes encounter numerous cellular proteins in the cytoplasm, which restrict viral infection and protect the nucleus. To overcome host cell defenses, the pathogens have evolved several evasion strategies. Viral proteins often contain nuclear localization signals, allowing entry into the nucleus. Among more than 1000 proteins identified as required for HIV infection by RNA interference screening, karyopherins, cleavage and polyadenylation specific factor 6, and nucleoporins have been predominantly studied. This review discusses current opinions about the synergistic relationship between the viral and cellular factors involved in nuclear import, with focus on the unveiled mysteries of the host–pathogen interaction, and highlights novel approaches to pinpoint therapeutic targets.
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Cauldwell, Anna V., Jason S. Long, Olivier Moncorgé, and Wendy S. Barclay. "Viral determinants of influenza A virus host range." Journal of General Virology 95, no. 6 (2014): 1193–210. http://dx.doi.org/10.1099/vir.0.062836-0.
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Typical avian influenza A viruses are restricted from replicating efficiently and causing disease in humans. However, an avian virus can become adapted to humans by mutating or recombining with currently circulating human viruses. These viruses have the potential to cause pandemics in an immunologically naïve human population. It is critical that we understand the molecular basis of host-range restriction and how this can be overcome. Here, we review our current understanding of the mechanisms by which influenza viruses adapt to replicate efficiently in a new host. We predominantly focus on the influenza polymerase, which remains one of the least understood host-range barriers.
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Busnadiego, Idoia, Melissa Kane, Suzannah J. Rihn, et al. "Host and Viral Determinants of Mx2 Antiretroviral Activity." Journal of Virology 88, no. 14 (2014): 7738–52. http://dx.doi.org/10.1128/jvi.00214-14.
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ABSTRACTMyxovirus resistance 2 (Mx2/MxB) has recently been uncovered as an effector of the anti-HIV-1 activity of type I interferons (IFNs) that inhibits HIV-1 at an early stage postinfection, after reverse transcription but prior to proviral integration into host DNA. The mechanistic details of Mx2 antiviral activity are not yet understood, but a few substitutions in the HIV-1 capsid have been shown to confer resistance to Mx2. Through a combination ofin vitroevolution and unbiased mutagenesis, we further map the determinants of sensitivity to Mx2 and reveal that multiple capsid (CA) surfaces define sensitivity to Mx2. Intriguingly, we reveal an unanticipated sensitivity determinant within the C-terminal domain of capsid. We also report that Mx2s derived from multiple primate species share the capacity to potently inhibit HIV-1, whereas selected nonprimate orthologs have no such activity. Like TRIM5α, another CA targeting antiretroviral protein, primate Mx2s exhibit species-dependent variation in antiviral specificity against at least one extant virus and multiple HIV-1 capsid mutants. Using a combination of chimeric Mx2 proteins and evolution-guided approaches, we reveal that a single residue close to the N terminus that has evolved under positive selection can determine antiviral specificity. Thus, the variable N-terminal region can define the spectrum of viruses inhibited by Mx2.IMPORTANCEType I interferons (IFNs) inhibit the replication of most mammalian viruses. IFN stimulation upregulates hundreds of different IFN-stimulated genes (ISGs), but it is often unclear which ISGs are responsible for inhibition of a given virus. Recently, Mx2 was identified as an ISG that contributes to the inhibition of HIV-1 replication by type I IFN. Thus, Mx2 might inhibit HIV-1 replication in patients, and this inhibitory action might have therapeutic potential. The mechanistic details of how Mx2 inhibits HIV-1 are currently unclear, but the HIV-1 capsid protein is the likely viral target. Here, we determine the regions of capsid that specify sensitivity to Mx2. We demonstrate that Mx2 from multiple primates can inhibit HIV-1, whereas Mx2 from other mammals (dogs and sheep) cannot. We also show that primate variants of Mx2 differ in the spectrum of lentiviruses they inhibit and that a single residue in Mx2 can determine this antiviral specificity.
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Van de Perre, Philippe. "Viral and host determinants of HIV-1 pathogenesis." AIDS 20, no. 6 (2006): 933–34. http://dx.doi.org/10.1097/01.aids.0000218560.67155.1c.
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Pillay, Sirika, and Jan E. Carette. "Host determinants of adeno-associated viral vector entry." Current Opinion in Virology 24 (June 2017): 124–31. http://dx.doi.org/10.1016/j.coviro.2017.06.003.
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Ketkar, Harshada, Daniella Herman, and Penghua Wang. "Genetic Determinants of the Re-Emergence of Arboviral Diseases." Viruses 11, no. 2 (2019): 150. http://dx.doi.org/10.3390/v11020150.
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Mosquito-borne diseases constitute a large portion of infectious diseases, causing more than 700,000 deaths annually. Mosquito-transmitted viruses, such as yellow fever, dengue, West Nile, chikungunya, and Zika viruses, have re-emerged recently and remain a public health threat worldwide. Global climate change, rapid urbanization, burgeoning international travel, expansion of mosquito populations, vector competence, and host and viral genetics may all together contribute to the re-emergence of arboviruses. In this brief review, we summarize the host and viral genetic determinants that may enhance infectivity in the host, viral fitness in mosquitoes and viral transmission by mosquitoes.
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LaTourrette, Katherine, and Hernan Garcia-Ruiz. "Determinants of Virus Variation, Evolution, and Host Adaptation." Pathogens 11, no. 9 (2022): 1039. http://dx.doi.org/10.3390/pathogens11091039.
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Virus evolution is the change in the genetic structure of a viral population over time and results in the emergence of new viral variants, strains, and species with novel biological properties, including adaptation to new hosts. There are host, vector, environmental, and viral factors that contribute to virus evolution. To achieve or fine tune compatibility and successfully establish infection, viruses adapt to a particular host species or to a group of species. However, some viruses are better able to adapt to diverse hosts, vectors, and environments. Viruses generate genetic diversity through mutation, reassortment, and recombination. Plant viruses are exposed to genetic drift and selection pressures by host and vector factors, and random variants or those with a competitive advantage are fixed in the population and mediate the emergence of new viral strains or species with novel biological properties. This process creates a footprint in the virus genome evident as the preferential accumulation of substitutions, insertions, or deletions in areas of the genome that function as determinants of host adaptation. Here, with respect to plant viruses, we review the current understanding of the sources of variation, the effect of selection, and its role in virus evolution and host adaptation.
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Graham, Jessica B., Jessica Swarts, Michael Mooney, and Jennifer M. Lund. "Immunogenetic determinants of HSV-2 infection and disease." Journal of Immunology 208, no. 1_Supplement (2022): 182.25. http://dx.doi.org/10.4049/jimmunol.208.supp.182.25.
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Abstract Herpes simplex virus-2 (HSV-2) is one of the most prevalent sexually transmitted infections, and can result in life-long, chronic disease. Disease severity, frequency of reactivation, and shedding rates vary between individuals, though little is known about how host genes regulate tissue-specific immune responses. We have previously used the Collaborative Cross (CC) mouse model system, which incorporates the extent of genetic variation found in the human genome, to better model the diversity of outcomes found in human viral infections, so we next probed the CC to identify host genetic regions that regulate viral shedding and disease following HSV-2 infection, as well as tissue-specific immune responses. We performed a screen of mice from different CC strains to assess viral titers and disease following vaginal HSV-2 infection, and then used this data to perform quantitative trait loci (QTL) mapping to identify chromosomal regions linked to vaginal viral shedding rates and levels, as well as virus-associated clinical disease. In parallel experiments, we assessed lymphoid, nervous system, and mucosal immune cell frequencies at innate, adaptive, and memory response timepoints. We observed a distinctive suppressive signature on vaginal Tregs compared to lymph node Tregs, at various times following HSV-2 infection. Additionally, these suppressive responses varied in mice with either higher viral titers, or more tissue inflammation, highlighting the interplay between host immune response and viral infection kinetics. Understanding host factors that contribute to HSV shedding, clinical disease, and immune responses may provide critical insights for developing new preventive strategies or interventions to HSV-2 infection. Supported by grant R21 AI152559-01 from the NIH
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Collins-McMillen, Donna, Jason Buehler, Megan Peppenelli, and Felicia Goodrum. "Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation." Viruses 10, no. 8 (2018): 444. http://dx.doi.org/10.3390/v10080444.
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Human cytomegalovirus (HCMV) is a beta herpesvirus that establishes a life-long persistence in the host, like all herpesviruses, by way of a latent infection. During latency, viral genomes are maintained in a quieted state. Virus replication can be reactivated from latency in response to changes in cellular signaling caused by stress or differentiation. The past decade has brought great insights into the molecular basis of HCMV latency. Here, we review the complex persistence of HCMV with consideration of latent reservoirs, viral determinants and their host interactions, and host signaling and the control of cellular and viral gene expression that contributes to the establishment of and reactivation from latency.
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Long, Jason S., Bhakti Mistry, Stuart M. Haslam, and Wendy S. Barclay. "Host and viral determinants of influenza A virus species specificity." Nature Reviews Microbiology 17, no. 2 (2018): 67–81. http://dx.doi.org/10.1038/s41579-018-0115-z.
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Kinast, Volker, Mara Klöhn, Maximilian K. Nocke, Daniel Todt, and Eike Steinmann. "Hepatitis E virus species barriers: seeking viral and host determinants." Current Opinion in Virology 56 (October 2022): 101274. http://dx.doi.org/10.1016/j.coviro.2022.101274.
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Streicker, Daniel G., Sonia M. Altizer, Andrés Velasco-Villa, and Charles E. Rupprecht. "Variable evolutionary routes to host establishment across repeated rabies virus host shifts among bats." Proceedings of the National Academy of Sciences 109, no. 48 (2012): 19715–20. https://doi.org/10.5281/zenodo.13426171.
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(Uploaded by Plazi for the Bat Literature Project) Determining the genetic pathways that viruses traverse to establish in new host species is crucial to predict the outcome of cross-species transmission but poorly understood for most host–virus systems. Using sequences encoding 78% of the rabies virus genome, we explored the extent, repeatability and dynamic outcome of evolution associated with multiple host shifts among New World bats. Episodic bursts of positive selection were detected in several viral proteins, including regions associated with host cell interaction and viral replication. Host shifts involved unique sets of substitutions, and few sites exhibited repeated evolution across adaptation to many bat species, suggesting diverse genetic determinants over host range. Combining these results with genetic reconstructions of the demographic histories of individual viral lineages revealed that although rabies viruses shared consistent three-stage processes of emergence in each new bat species, host shifts involving greater numbers of positively selected substitutions had longer delays between cross-species transmission and enzootic viral establishment. Our results point to multiple evolutionary routes to host establishment in a zoonotic RNA virus that may influence the speed of viral emergence.
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Streicker, Daniel G., Sonia M. Altizer, Andrés Velasco-Villa, and Charles E. Rupprecht. "Variable evolutionary routes to host establishment across repeated rabies virus host shifts among bats." Proceedings of the National Academy of Sciences 109, no. 48 (2012): 19715–20. https://doi.org/10.5281/zenodo.13426171.
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(Uploaded by Plazi for the Bat Literature Project) Determining the genetic pathways that viruses traverse to establish in new host species is crucial to predict the outcome of cross-species transmission but poorly understood for most host–virus systems. Using sequences encoding 78% of the rabies virus genome, we explored the extent, repeatability and dynamic outcome of evolution associated with multiple host shifts among New World bats. Episodic bursts of positive selection were detected in several viral proteins, including regions associated with host cell interaction and viral replication. Host shifts involved unique sets of substitutions, and few sites exhibited repeated evolution across adaptation to many bat species, suggesting diverse genetic determinants over host range. Combining these results with genetic reconstructions of the demographic histories of individual viral lineages revealed that although rabies viruses shared consistent three-stage processes of emergence in each new bat species, host shifts involving greater numbers of positively selected substitutions had longer delays between cross-species transmission and enzootic viral establishment. Our results point to multiple evolutionary routes to host establishment in a zoonotic RNA virus that may influence the speed of viral emergence.
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Streicker, Daniel G., Sonia M. Altizer, Andrés Velasco-Villa, and Charles E. Rupprecht. "Variable evolutionary routes to host establishment across repeated rabies virus host shifts among bats." Proceedings of the National Academy of Sciences 109, no. 48 (2012): 19715–20. https://doi.org/10.5281/zenodo.13426171.
Full textAbstract:
(Uploaded by Plazi for the Bat Literature Project) Determining the genetic pathways that viruses traverse to establish in new host species is crucial to predict the outcome of cross-species transmission but poorly understood for most host–virus systems. Using sequences encoding 78% of the rabies virus genome, we explored the extent, repeatability and dynamic outcome of evolution associated with multiple host shifts among New World bats. Episodic bursts of positive selection were detected in several viral proteins, including regions associated with host cell interaction and viral replication. Host shifts involved unique sets of substitutions, and few sites exhibited repeated evolution across adaptation to many bat species, suggesting diverse genetic determinants over host range. Combining these results with genetic reconstructions of the demographic histories of individual viral lineages revealed that although rabies viruses shared consistent three-stage processes of emergence in each new bat species, host shifts involving greater numbers of positively selected substitutions had longer delays between cross-species transmission and enzootic viral establishment. Our results point to multiple evolutionary routes to host establishment in a zoonotic RNA virus that may influence the speed of viral emergence.
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Mlera, Luwanika, Melissa Moy, Kristen Maness, Linh N. Tran, and Felicia D. Goodrum. "The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation." Viruses 12, no. 7 (2020): 714. http://dx.doi.org/10.3390/v12070714.
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Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of latency and reactivation and their host interactions that govern the latent state and reactivation from latency have been identified. The polycistronic UL133-UL138 locus encodes determinants of both latency and reactivation. In this review, we survey the model systems used to investigate latency and new findings from these systems. Particular focus is given to the roles of the UL133, UL135, UL136 and UL138 proteins in regulating viral latency and how their known host interactions contribute to regulating host signaling pathways towards the establishment of or exit from latency. Understanding the mechanisms underlying viral latency and reactivation is important in developing strategies to block reactivation and prevent CMV disease in immunocompromised individuals, such as transplant patients.
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Streicker, Daniel G., Amy S. Turmelle, Maarten J. Vonhof, Ivan V. Kuzmin, Gary F. McCracken, and Charles E. Rupprecht. "Host Phylogeny Constrains Cross-Species Emergence and Establishment of Rabies Virus in Bats." Science 329, no. 5992 (2010): 676–79. https://doi.org/10.5281/zenodo.14816864.
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(Uploaded by Plazi for the Bat Literature Project) For RNA viruses, rapid viral evolution and the biological similarity of closely related host species have been proposed as key determinants of the occurrence and long-term outcome of cross-species transmission. Using a data set of hundreds of rabies viruses sampled from 23 North American bat species, we present a general framework to quantify per capita rates of cross-species transmission and reconstruct historical patterns of viral establishment in new host species using molecular sequence data. These estimates demonstrate diminishing frequencies of both cross-species transmission and host shifts with increasing phylogenetic distance between bat species. Evolutionary constraints on viral host range indicate that host species barriers may trump the intrinsic mutability of RNA viruses in determining the fate of emerging host-virus interactions.
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Primadharsini, Putu Prathiwi, Shigeo Nagashima, and Hiroaki Okamoto. "Mechanism of Cross-Species Transmission, Adaptive Evolution and Pathogenesis of Hepatitis E Virus." Viruses 13, no. 5 (2021): 909. http://dx.doi.org/10.3390/v13050909.
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Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. While the transmission in developing countries is dominated by fecal-oral route via drinking contaminated water, the zoonotic transmission is the major route of HEV infection in industrialized countries. The discovery of new HEV strains in a growing number of animal species poses a risk to zoonotic infection. However, the exact mechanism and the determinant factors of zoonotic infection are not completely understood. This review will discuss the current knowledge on the mechanism of cross-species transmission of HEV infection, including viral determinants, such as the open reading frames (ORFs), codon usage and adaptive evolution, as well as host determinants, such as host cellular factors and the host immune status, which possibly play pivotal roles during this event. The pathogenesis of hepatitis E infection will be briefly discussed, including the special forms of this disease, including extrahepatic manifestations, chronic infection, and fulminant hepatitis in pregnant women.
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Ahlquist, Paul, Michael Schwartz, Jianbo Chen, David Kushner, Linhui Hao, and Billy T. Dye. "Viral and host determinants of RNA virus vector replication and expression." Vaccine 23, no. 15 (2005): 1784–87. http://dx.doi.org/10.1016/j.vaccine.2004.11.005.
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Stier, Matthew T., and R. Stokes Peebles. "Host and Viral Determinants of Respiratory Syncytial Virus-induced Airway Mucus." Annals of the American Thoracic Society 15, Supplement_3 (2018): S205—S209. http://dx.doi.org/10.1513/annalsats.201806-380aw.
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Calvo, María, Sandra Martínez-Turiño, and Juan Antonio García. "Resistance to Plum pox virus Strain C in Arabidopsis thaliana and Chenopodium foetidum Involves Genome-Linked Viral Protein and Other Viral Determinants and Might Depend on Compatibility With Host Translation Initiation Factors." Molecular Plant-Microbe Interactions® 27, no. 11 (2014): 1291–301. http://dx.doi.org/10.1094/mpmi-05-14-0130-r.
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Research performed on model herbaceous hosts has been useful to unravel the molecular mechanisms that control viral infections. The most common Plum pox virus (PPV) strains are able to infect Nicotiana species as well as Chenopodium and Arabidopsis species. However, isolates belonging to strain C (PPV-C) that have been adapted to Nicotiana spp. are not infectious either in Chenopodium foetidum or in Arabidopsis thaliana. In order to determine the mechanism underlying this interesting host-specific behavior, we have constructed chimerical clones derived from Nicotiana-adapted PPV isolates from the D and C strains, which differ in their capacity to infect A. thaliana and C. foetidum. With this approach, we have identified the nuclear inclusion a protein (VPg+Pro) as the major pathogenicity determinant that conditions resistance in the presence of additional secondary determinants, different for each host. Genome-linked viral protein (VPg) mutations similar to those involved in the breakdown of eIF4E-mediated resistance to other potyviruses allow some PPV chimeras to infect A. thaliana. These results point to defective interactions between a translation initiation factor and the viral VPg as the most probable cause of host-specific incompatibility, in which other viral factors also participate, and suggest that complex interactions between multiple viral proteins and translation initiation factors not only define resistance to potyviruses in particular varieties of susceptible hosts but also contribute to establish nonhost resistance.
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Eisenlohr, L. C., W. Gerhard, and C. J. Hackett. "Acid-induced conformational modification of the hemagglutinin molecule alters interaction of influenza virus with antigen-presenting cells." Journal of Immunology 141, no. 6 (1988): 1870–76. http://dx.doi.org/10.4049/jimmunol.141.6.1870.
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Abstract Brief exposure of influenza virus to pH 5 was found to have extensive effects upon presentation of viral Th cell antigenic determinants. This acidity, comparable to that encountered in host cell endosomes, was known to effect conformational changes in the viral hemagglutinin (HA) which alter the molecule's fusion activity, antigenicity, and susceptibility to enzymes. Three major effects of low pH upon presentation of viral T cell determinants were observed: first, acid pretreatment permitted presentation by pre-fixed APC of two of three linear T cell sites of the HA molecule, bypassing the APC activity required to present untreated virus; second, the two determinants presented in this manner disappeared rapidly from APC surfaces; third, acid-pretreated virus was not efficiently utilized by active APC in the normal pathway of viral antigen presentation. These observations suggest that the pH-induced conformational transition of HA may constitute sufficient processing for certain linear determinants of the molecule and additionally influences the processes involved in the general formation and presentation of viral T cell sites.
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Barth, Heidi, Eva K. Schnober, Fuming Zhang, et al. "Viral and Cellular Determinants of the Hepatitis C Virus Envelope-Heparan SulfateInteraction." Journal of Virology 80, no. 21 (2006): 10579–90. http://dx.doi.org/10.1128/jvi.00941-06.
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ABSTRACT Cellular binding and entry of hepatitis C virus (HCV) are the first steps of viral infection and represent a major target for antiviral antibodies and novel therapeutic strategies. We have recently demonstrated that heparan sulfate (HS) plays a key role in the binding of HCV envelope glycoprotein E2 to target cells (Barth et al., J. Biol. Chem. 278:41003-41012, 2003). In this study, we characterized the HCV-HS interaction and analyzed its inhibition by antiviral host immune responses. Using recombinant envelope glycoproteins, virus-like particles, and HCV pseudoparticles as model systems for the early steps of viral infection, we mapped viral and cellular determinants of HCV-HS interaction. HCV-HS binding required a specific HS structure that included N-sulfo groups and a minimum of 10 to 14 saccharide subunits. HCV envelope binding to HS was mediated by four viral epitopes overlapping the E2 hypervariable region 1 and E2-CD81 binding domains. In functional studies using HCV pseudoparticles, we demonstrate that HCV binding and entry are specifically inhibited by highly sulfated HS. Finally, HCV-HS binding was markedly inhibited by antiviral antibodies derived from HCV-infected individuals. In conclusion, our results demonstrate that binding of the viral envelope to a specific HS configuration represents an important step for the initiation of viral infection and is a target of antiviral host immune responses in vivo. Mapping of viral and cellular determinants of HCV-HS interaction sets the stage for the development of novel HS-based antiviral strategies targeting viral attachment and entry.
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Brown, Emily E. F., Reza Rezaei, Taylor R. Jamieson, et al. "Characterization of Critical Determinants of ACE2–SARS CoV-2 RBD Interaction." International Journal of Molecular Sciences 22, no. 5 (2021): 2268. http://dx.doi.org/10.3390/ijms22052268.
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Despite sequence similarity to SARS-CoV-1, SARS-CoV-2 has demonstrated greater widespread virulence and unique challenges to researchers aiming to study its pathogenicity in humans. The interaction of the viral receptor binding domain (RBD) with its main host cell receptor, angiotensin-converting enzyme 2 (ACE2), has emerged as a critical focal point for the development of anti-viral therapeutics and vaccines. In this study, we selectively identify and characterize the impact of mutating certain amino acid residues in the RBD of SARS-CoV-2 and in ACE2, by utilizing our recently developed NanoBiT technology-based biosensor as well as pseudotyped-virus infectivity assays. Specifically, we examine the mutational effects on RBD-ACE2 binding ability, efficacy of competitive inhibitors, as well as neutralizing antibody activity. We also look at the implications the mutations may have on virus transmissibility, host susceptibility, and the virus transmission path to humans. These critical determinants of virus–host interactions may provide more effective targets for ongoing vaccines, drug development, and potentially pave the way for determining the genetic variation underlying disease severity.
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Long, Jason S., Bhakti Mistry, Stuart M. Haslam, and Wendy S. Barclay. "Publisher Correction: Host and viral determinants of influenza A virus species specificity." Nature Reviews Microbiology 17, no. 2 (2018): 124. http://dx.doi.org/10.1038/s41579-018-0140-y.
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Rapicetta, Maria, Carlo Ferrari, and Massimo Levrero. "Viral determinants and host immune responses in the pathogenesis of HBV infection." Journal of Medical Virology 67, no. 3 (2002): 454–57. http://dx.doi.org/10.1002/jmv.10096.
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Salazar, Stephanie, Khanh T. Y. Luong, and Orkide O. Koyuncu. "Cell Intrinsic Determinants of Alpha Herpesvirus Latency and Pathogenesis in the Nervous System." Viruses 15, no. 12 (2023): 2284. http://dx.doi.org/10.3390/v15122284.
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Alpha herpesvirus infections (α-HVs) are widespread, affecting more than 70% of the adult human population. Typically, the infections start in the mucosal epithelia, from which the viral particles invade the axons of the peripheral nervous system. In the nuclei of the peripheral ganglia, α-HVs establish a lifelong latency and eventually undergo multiple reactivation cycles. Upon reactivation, viral progeny can move into the nerves, back out toward the periphery where they entered the organism, or they can move toward the central nervous system (CNS). This latency–reactivation cycle is remarkably well controlled by the intricate actions of the intrinsic and innate immune responses of the host, and finely counteracted by the viral proteins in an effort to co-exist in the population. If this yin-yang- or Nash-equilibrium-like balance state is broken due to immune suppression or genetic mutations in the host response factors particularly in the CNS, or the presence of other pathogenic stimuli, α-HV reactivations might lead to life-threatening pathologies. In this review, we will summarize the molecular virus–host interactions starting from mucosal epithelia infections leading to the establishment of latency in the PNS and to possible CNS invasion by α-HVs, highlighting the pathologies associated with uncontrolled virus replication in the NS.
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Handa, Tanuj, Ankita Saha, Aarthi Narayanan, et al. "Structural Virology: The Key Determinants in Development of Antiviral Therapeutics." Viruses 17, no. 3 (2025): 417. https://doi.org/10.3390/v17030417.
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Structural virology has emerged as the foundation for the development of effective antiviral therapeutics. It is pivotal in providing crucial insights into the three-dimensional frame of viruses and viral proteins at atomic-level or near-atomic-level resolution. Structure-based assessment of viral components, including capsids, envelope proteins, replication machinery, and host interaction interfaces, is instrumental in unraveling the multiplex mechanisms of viral infection, replication, and pathogenesis. The structural elucidation of viral enzymes, including proteases, polymerases, and integrases, has been essential in combating viruses like HIV-1 and HIV-2, SARS-CoV-2, and influenza. Techniques including X-ray crystallography, Nuclear Magnetic Resonance spectroscopy, Cryo-electron Microscopy, and Cryo-electron Tomography have revolutionized the field of virology and significantly aided in the discovery of antiviral therapeutics. The ubiquity of chronic viral infections, along with the emergence and reemergence of new viral threats necessitate the development of novel antiviral strategies and agents, while the extensive structural diversity of viruses and their high mutation rates further underscore the critical need for structural analysis of viral proteins to aid antiviral development. This review highlights the significance of structure-based investigations for bridging the gap between structure and function, thus facilitating the development of effective antiviral therapeutics, vaccines, and antibodies for tackling emerging viral threats.
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Humphreys, Daniel, Mohamed ElGhazaly, and Teresa Frisan. "Senescence and Host–Pathogen Interactions." Cells 9, no. 7 (2020): 1747. http://dx.doi.org/10.3390/cells9071747.
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Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.
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Kitchen, Andrew, Laura A. Shackelton, and Edward C. Holmes. "Family level phylogenies reveal modes of macroevolution in RNA viruses." Proceedings of the National Academy of Sciences 108, no. 1 (2010): 238–43. http://dx.doi.org/10.1073/pnas.1011090108.
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Despite advances in understanding the patterns and processes of microevolution in RNA viruses, little is known about the determinants of viral diversification at the macroevolutionary scale. In particular, the processes by which viral lineages assigned as different “species” are generated remain largely uncharacterized. To address this issue, we use a robust phylogenetic approach to analyze patterns of lineage diversification in five representative families of RNA viruses. We ask whether the process of lineage diversification primarily occurs when viruses infect new host species, either through cross-species transmission or codivergence, and which are defined here as analogous to allopatric speciation in animals, or by acquiring new niches within the same host species, analogous to sympatric speciation. By mapping probable primary host species onto family level viral phylogenies, we reveal a strong clustering among viral lineages that infect groups of closely related host species. Although this is consistent with lineage diversification within individual hosts, we argue that this pattern more likely represents strong biases in our knowledge of viral biodiversity, because we also find that better-sampled human viruses rarely cluster together. Hence, although closely related viruses tend to infect related host species, it is unlikely that they often infect the same host species, such that evolutionary constraints hinder lineage diversification within individual host species. We conclude that the colonization of new but related host species may represent the principle mode of macroevolution in RNA viruses.
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Moriyama, Miyu, Walter J. Hugentobler, and Akiko Iwasaki. "Seasonality of Respiratory Viral Infections." Annual Review of Virology 7, no. 1 (2020): 83–101. http://dx.doi.org/10.1146/annurev-virology-012420-022445.
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The seasonal cycle of respiratory viral diseases has been widely recognized for thousands of years, as annual epidemics of the common cold and influenza disease hit the human population like clockwork in the winter season in temperate regions. Moreover, epidemics caused by viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and the newly emerging SARS-CoV-2 occur during the winter months. The mechanisms underlying the seasonal nature of respiratory viral infections have been examined and debated for many years. The two major contributing factors are the changes in environmental parameters and human behavior. Studies have revealed the effect of temperature and humidity on respiratory virus stability and transmission rates. More recent research highlights the importance of the environmental factors, especially temperature and humidity, in modulating host intrinsic, innate, and adaptive immune responses to viral infections in the respiratory tract. Here we review evidence of how outdoor and indoor climates are linked to the seasonality of viral respiratory infections. We further discuss determinants of host response in the seasonality of respiratory viruses by highlighting recent studies in the field.
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Gallo, Giovanna Lucrecia, Nora López, and María Eugenia Loureiro. "The Virus–Host Interplay in Junín Mammarenavirus Infection." Viruses 14, no. 6 (2022): 1134. http://dx.doi.org/10.3390/v14061134.
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Junín virus (JUNV) belongs to the Arenaviridae family and is the causative agent of Argentine hemorrhagic fever (AHF), a severe human disease endemic to agricultural areas in Argentina. At this moment, there are no effective antiviral therapeutics to battle pathogenic arenaviruses. Cumulative reports from recent years have widely provided information on cellular factors playing key roles during JUNV infection. In this review, we summarize research on host molecular determinants that intervene in the different stages of the viral life cycle: viral entry, replication, assembly and budding. Alongside, we describe JUNV tight interplay with the innate immune system. We also review the development of different reverse genetics systems and their use as tools to study JUNV biology and its close teamwork with the host. Elucidating relevant interactions of the virus with the host cell machinery is highly necessary to better understand the mechanistic basis beyond virus multiplication, disease pathogenesis and viral subversion of the immune response. Altogether, this knowledge becomes essential for identifying potential targets for the rational design of novel antiviral treatments to combat JUNV as well as other pathogenic arenaviruses.
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LaPointe, Autumn T., and Kevin J. Sokoloski. "De-Coding the Contributions of the Viral RNAs to Alphaviral Pathogenesis." Pathogens 10, no. 6 (2021): 771. http://dx.doi.org/10.3390/pathogens10060771.
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Alphaviruses are positive-sense RNA arboviruses that are capable of causing severe disease in otherwise healthy individuals. There are many aspects of viral infection that determine pathogenesis and major efforts regarding the identification and characterization of virulence determinants have largely focused on the roles of the nonstructural and structural proteins. Nonetheless, the viral RNAs of the alphaviruses themselves play important roles in regard to virulence and pathogenesis. In particular, many sequences and secondary structures within the viral RNAs play an important part in the development of disease and may be considered important determinants of virulence. In this review article, we summarize the known RNA-based virulence traits and host:RNA interactions that influence alphaviral pathogenesis for each of the viral RNA species produced during infection. Overall, the viral RNAs produced during infection are important contributors to alphaviral pathogenesis and more research is needed to fully understand how each RNA species impacts the host response to infection as well as the development of disease.
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Nennig, Kylie, Satyapramod Murthy, Sara Maloney, et al. "Determinants of pegivirus persistence, cross-species infection, and adaptation in the laboratory mouse." PLOS Pathogens 20, no. 8 (2024): e1012436. http://dx.doi.org/10.1371/journal.ppat.1012436.
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Viruses capable of causing persistent infection have developed sophisticated mechanisms for evading host immunity, and understanding these processes can reveal novel features of the host immune system. One such virus, human pegivirus (HPgV), infects ~15% of the global human population, but little is known about its biology beyond the fact that it does not cause overt disease. We passaged a pegivirus isolate of feral brown rats (RPgV) in immunodeficient laboratory mice to develop a mouse-adapted virus (maPgV) that established persistent high-titer infection in a majority of wild-type laboratory mice. maRPgV viremia was detected in the blood of mice for >300 days without apparent disease, closely recapitulating the hallmarks of HPgV infection in humans. We found a pro-viral role for type-I interferon in chronic infection; a lack of PD-1-mediated tolerance to PgV infection; and multiple mechanisms by which PgV immunity can be achieved by an immunocompetent host. These data indicate that the PgV immune evasion strategy has aspects that are both common and unique among persistent viral infections. The creation of maPgV represents the first PgV infection model in wild-type mice, thus opening the entire toolkit of the mouse host to enable further investigation of this persistent RNA virus infections.
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Iwamoto, Tokinori, Yasushi Okinaka, Kazuyuki Mise, et al. "Identification of Host-Specificity Determinants in Betanodaviruses by Using Reassortants between Striped Jack Nervous Necrosis Virus and Sevenband Grouper Nervous Necrosis Virus." Journal of Virology 78, no. 3 (2004): 1256–62. http://dx.doi.org/10.1128/jvi.78.3.1256-1262.2004.
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ABSTRACT Betanodaviruses, the causal agents of viral nervous necrosis in marine fish, have bipartite positive-sense RNAs as genomes. The larger genomic segment, RNA1 (3.1 kb), encodes an RNA-dependent RNA polymerase, and the smaller genomic segment, RNA2 (1.4 kb), codes for the coat protein. Betanodaviruses have marked host specificity, although the primary structures of the viral RNAs and encoded proteins are similar among betanodaviruses. However, no mechanism underlying the host specificity has yet been reported. To evaluate viral factors that control host specificity, we first constructed a cDNA-mediated infectious RNA transcription system for sevenband grouper nervous necrosis virus (SGNNV) in addition to that for striped jack nervous necrosis virus (SJNNV), which was previously established by us. We then tested two reassortants between SJNNV and SGNNV for infectivity in the host fish from which they originated. When striped jack and sevenband grouper larvae were bath challenged with the reassortant virus comprising SJNNV RNA1 and SGNNV RNA2, sevenband groupers were killed exclusively, similar to inoculation with SGNNV. Conversely, inoculations with the reassortant virus comprising SGNNV RNA1 and SJNNV RNA2 killed striped jacks but did not affect sevenband groupers. Immunofluorescence microscopic studies using anti-SJNNV polyclonal antibodies revealed that both of the reassortants multiplied in the brains, spinal cords, and retinas of infected fish, similar to infections with parental virus inoculations. These results indicate that viral RNA2 and/or encoded coat protein controls host specificity in SJNNV and SGNNV.
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Lisy, Samantha, Katherine Rothamel, and Manuel Ascano. "RNA Binding Proteins as Pioneer Determinants of Infection: Protective, Proviral, or Both?" Viruses 13, no. 11 (2021): 2172. http://dx.doi.org/10.3390/v13112172.
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As the first intracellular host factors that directly interact with the genomes of RNA viruses, RNA binding proteins (RBPs) have a profound impact on the outcome of an infection. Recent discoveries brought about by new methodologies have led to an unprecedented ability to peer into the earliest events between viral RNA and the RBPs that act upon them. These discoveries have sparked a re-evaluation of current paradigms surrounding RBPs and post-transcriptional gene regulation. Here, we highlight questions that have bloomed from the implementation of these novel approaches. Canonical RBPs can impact the fates of both cellular and viral RNA during infection, sometimes in conflicting ways. Noncanonical RBPs, some of which were first characterized via interactions with viral RNA, may encompass physiological roles beyond viral pathogenesis. We discuss how these RBPs might discriminate between an RNA of either cellular or viral origin and thus exert either pro- or antiviral effects—which is a particular challenge as viruses contain mechanisms to mimic molecular features of cellular RNA.
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Maharaj, Payal D., Angela M. Bosco-Lauth, Stanley A. Langevin, et al. "West Nile and St. Louis encephalitis viral genetic determinants of avian host competence." PLOS Neglected Tropical Diseases 12, no. 2 (2018): e0006302. http://dx.doi.org/10.1371/journal.pntd.0006302.
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Kaur, Ramandeep, Jyoti Batra, Olga Stuchlik, et al. "Heterogeneous Ribonucleoprotein A1 (hnRNPA1) Interacts with the Nucleoprotein of the Influenza a Virus and Impedes Virus Replication." Viruses 14, no. 2 (2022): 199. http://dx.doi.org/10.3390/v14020199.
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Influenza A virus (IAV), like other viruses, depends on the host cellular machinery for replication and production of progeny. The relationship between a virus and a host is complex, shaped by many spatial and temporal interactions between viral and host proteome, ultimately dictating disease outcome. Therefore, it is imperative to identify host-virus interactions as crucial determinants of disease pathogenies. Heterogeneous ribonucleoprotein A1 (hnRNPA1) is an RNA binding protein involved in the life cycle of many DNA and RNA viruses; however, its role in IAV remains undiscovered. Here we report that human hnRNPA1 physically interacts with the nucleoprotein (NP) of IAV in mammalian cells at different time points of the viral replication cycle. Temporal distribution studies identify hnRNPA1 and NP co-localize in the same cellular milieu in both nucleus and mitochondria in NP-transfected and IAV-infected mammalian cells. Interestingly, hnRNPA1 influenced NP gene expression and affected viral replication. Most importantly, hnRNPA1 knockdown caused a significant increase in NP expression and enhanced viral replication (93.82%) in IAV infected A549 cells. Conversely, hnRNPA1 overexpression reduced NP expression at the mRNA and protein levels and impeded virus replication by (60.70%), suggesting antagonistic function. Taken together, results from this study demonstrate that cellular hnRNPA1 plays a protective role in the host hitherto unknown and may hold potential as an antiviral target to develop host-based therapeutics against IAV.
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Lane, Rebecca K., Hongyan Guo, Amanda D. Fisher, et al. "Necroptosis-based CRISPR knockout screen reveals Neuropilin-1 as a critical host factor for early stages of murine cytomegalovirus infection." Proceedings of the National Academy of Sciences 117, no. 33 (2020): 20109–16. http://dx.doi.org/10.1073/pnas.1921315117.
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Herpesviruses are ubiquitous human pathogens that cause a wide range of health complications. Currently, there is an incomplete understanding of cellular factors that contribute to herpesvirus infection. Here, we report an antiviral necroptosis-based genetic screen to identify novel host cell factors required for infection with the β-herpesvirus murine cytomegalovirus (MCMV). Our genome-wide CRISPR-based screen harnessed the capacity of herpesvirus mutants that trigger antiviral necroptotic cell death upon early viral gene expression. Vascular endothelial growth factor (VEGF) and semaphorin-binding receptor Neuropilin-1 (Nrp-1) emerge as crucial determinants of MCMV infection. We find that elimination of Nrp-1 impairs early viral gene expression and reduces infection rates in endothelial cells, fibroblasts, and macrophages. Furthermore, preincubation of virus with soluble Nrp-1 dramatically inhibits infection by reducing virus attachment. Thus, Nrp-1 is a key determinant of the initial phase of MCMV infection.
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Das Sarma, Jayasri, Li Fu, Jean C. Tsai, Susan R. Weiss, and Ehud Lavi. "Demyelination Determinants Map to the Spike Glycoprotein Gene of Coronavirus Mouse Hepatitis Virus." Journal of Virology 74, no. 19 (2000): 9206–13. http://dx.doi.org/10.1128/jvi.74.19.9206-9213.2000.
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ABSTRACT Demyelination is the pathologic hallmark of the human immune-mediated neurologic disease multiple sclerosis, which may be triggered or exacerbated by viral infections. Several experimental animal models have been developed to study the mechanism of virus-induced demyelination, including coronavirus mouse hepatitis virus (MHV) infection in mice. The envelope spike (S) glycoprotein of MHV contains determinants of properties essential for virus-host interactions. However, the molecular determinants of MHV-induced demyelination are still unknown. To investigate the mechanism of MHV-induced demyelination, we examined whether the S gene of MHV contains determinants of demyelination and whether demyelination is linked to viral persistence. Using targeted RNA recombination, we replaced the S gene of a demyelinating virus (MHV-A59) with the S gene of a closely related, nondemyelinating virus (MHV-2). Recombinant viruses containing an S gene derived from MHV-2 in an MHV-A59 background (Penn98-1 and Penn98-2) exhibited a persistence-positive, demyelination-negative phenotype. Thus, determinants of demyelination map to the S gene of MHV. Furthermore, viral persistence is insufficient to induce demyelination, although it may be a prerequisite for the development of demyelination.
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Carsillo, Thomas, Zachary Traylor, Changsun Choi, Stefan Niewiesk, and Michael Oglesbee. "hsp72, a Host Determinant of Measles Virus Neurovirulence." Journal of Virology 80, no. 22 (2006): 11031–39. http://dx.doi.org/10.1128/jvi.01438-06.
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ABSTRACT Transient hyperthermia such as that experienced during febrile episodes increases expression of the major inducible 70-kDa heat shock protein (hsp72). Despite the relevance of febrile episodes to viral pathogenesis and the multiple in vitro roles of heat shock proteins in viral replication and gene expression, the in vivo significance of virus-heat shock protein interactions is unknown. The present work determined the in vivo relationship between hsp72 levels and neurovirulence of an hsp72-responsive virus using the mouse model of measles virus (MV) encephalitis. Transgenic C57BL/6 mice were created to constitutively overexpress hsp72 in neurons, and these mice were inoculated intracranially with Edmonston MV (Ed MV) at 42 h of age. The mean viral RNA burden in brain was approximately 2 orders of magnitude higher in transgenic animals than in nontransgenic animals 2 to 4 weeks postinfection, and this increased burden was associated with a fivefold increase in mortality. Mice were also challenged with an Ed MV variant exhibiting an attenuated in vitro response to hsp72-dependent stimulation of viral transcription (Ed N-522D). This virus exhibited an attenuated neuropathogenicity in transgenic mice, where mortality and viral RNA burdens were not significantly different from nontransgenic mice infected with either Ed N-522D or parent Ed MV. Collectively, these results indicate that hsp72 levels can serve as a host determinant of viral neurovirulence in C57BL/6 mice, reflecting the direct influence of hsp72 on viral gene expression.
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Elkhalifa, Ahmed M. E., Showkat Ul Nabi, Ovais Shabir Shah, et al. "Insight into Oncogenic Viral Pathways as Drivers of Viral Cancers: Implication for Effective Therapy." Current Oncology 30, no. 2 (2023): 1924–44. http://dx.doi.org/10.3390/curroncol30020150.
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As per a recent study conducted by the WHO, 15.4% of all cancers are caused by infectious agents of various categories, and more than 10% of them are attributed to viruses. The emergence of COVID-19 has once again diverted the scientific community’s attention toward viral diseases. Some researchers have postulated that SARS-CoV-2 will add its name to the growing list of oncogenic viruses in the long run. However, owing to the complexities in carcinogenesis of viral origin, researchers across the world are struggling to identify the common thread that runs across different oncogenic viruses. Classical pathways of viral oncogenesis have identified oncogenic mediators in oncogenic viruses, but these mediators have been reported to act on diverse cellular and multiple omics pathways. In addition to viral mediators of carcinogenesis, researchers have identified various host factors responsible for viral carcinogenesis. Henceforth owing to viral and host complexities in viral carcinogenesis, a singular mechanistic pathway remains yet to be established; hence there is an urgent need to integrate concepts from system biology, cancer microenvironment, evolutionary perspective, and thermodynamics to understand the role of viruses as drivers of cancer. In the present manuscript, we provide a holistic view of the pathogenic pathways involved in viral oncogenesis with special emphasis on alteration in the tumor microenvironment, genomic alteration, biological entropy, evolutionary selection, and host determinants involved in the pathogenesis of viral tumor genesis. These concepts can provide important insight into viral cancers, which can have an important implication for developing novel, effective, and personalized therapeutic options for treating viral cancers.
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Foeglein, Ágnes, Eva M. Loucaides, Manuela Mura, Helen M. Wise, Wendy S. Barclay, and Paul Digard. "Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase." Journal of General Virology 92, no. 7 (2011): 1650–61. http://dx.doi.org/10.1099/vir.0.031492-0.
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Avian influenza A viruses often do not propagate efficiently in mammalian cells. The viral polymerase protein PB2 is important for this host restriction, with amino-acid polymorphisms at residue 627 and other positions acting as ‘signatures’ of avian- or human-adapted viruses. Restriction is hypothesized to result from differential interactions (either positive or inhibitory) with unidentified cellular factors. We applied fluorescence recovery after photobleaching (FRAP) to investigate the mobility of the viral polymerase in the cell nucleus using A/PR/8/34 and A/Turkey/England/50-92/91 as model strains. As expected, transcriptional activity of a polymerase with the avian PB2 protein was strongly dependent on the identity of residue 627 in human but not avian cells, and this correlated with significantly slower diffusion of the inactive polymerase in human but not avian nuclei. In contrast, the activity and mobility of the PR8 polymerase was affected much less by residue 627. Sequence comparison followed by mutagenic analyses identified residues at known host-range-specific positions 271, 588 and 701 as well as a novel determinant at position 636 as contributors to host-specific activity of both PR8 and Turkey PB2 proteins. Furthermore, the correlation between poor transcriptional activity and slow diffusional mobility was maintained. However, activity did not obligatorily correlate with predicted surface charge of the 627 domain. Overall, our data support the hypothesis of a host nuclear factor that interacts with the viral polymerase and modulates its activity. While we cannot distinguish between positive and inhibitory effects, the data have implications for how such factors might operate.
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Pekarek, Matthew J., and Eric A. Weaver. "Existing Evidence for Influenza B Virus Adaptations to Drive Replication in Humans as the Primary Host." Viruses 15, no. 10 (2023): 2032. http://dx.doi.org/10.3390/v15102032.
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Influenza B virus (IBV) is one of the two major types of influenza viruses that circulate each year. Unlike influenza A viruses, IBV does not harbor pandemic potential due to its lack of historical circulation in non-human hosts. Many studies and reviews have highlighted important factors for host determination of influenza A viruses. However, much less is known about the factors driving IBV replication in humans. We hypothesize that similar factors influence the host restriction of IBV. Here, we compile and review the current understanding of host factors crucial for the various stages of the IBV viral replication cycle. While we discovered the research in this area of IBV is limited, we review known host factors that may indicate possible host restriction of IBV to humans. These factors include the IBV hemagglutinin (HA) protein, host nuclear factors, and viral immune evasion proteins. Our review frames the current understanding of IBV adaptations to replication in humans. However, this review is limited by the amount of research previously completed on IBV host determinants and would benefit from additional future research in this area.
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Hoch, Nicolas C. "Host ADP-ribosylation and the SARS-CoV-2 macrodomain." Biochemical Society Transactions 49, no. 4 (2021): 1711–21. http://dx.doi.org/10.1042/bst20201212.
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The COVID-19 pandemic has prompted intense research efforts into elucidating mechanisms of coronavirus pathogenesis and to propose antiviral interventions. The interferon (IFN) response is the main antiviral component of human innate immunity and is actively suppressed by several non-structural SARS-CoV-2 proteins, allowing viral replication within human cells. Differences in IFN signalling efficiency and timing have emerged as central determinants of the variability of COVID-19 disease severity between patients, highlighting the need for an improved understanding of host–pathogen interactions that affect the IFN response. ADP-ribosylation is an underexplored post-translational modification catalyzed by ADP-ribosyl transferases collectively termed poly(ADP-ribose) polymerases (PARPs). Several human PARPs are induced by the IFN response and participate in antiviral defences by regulating IFN signalling itself, modulating host processes such as translation and protein trafficking, as well as directly modifying and inhibiting viral target proteins. SARS-CoV-2 and other viruses encode a macrodomain that hydrolyzes ADP-ribose modifications, thus counteracting antiviral PARP activity. This mini-review provides a brief overview of the known targets of IFN-induced ADP-ribosylation and the functions of viral macrodomains, highlighting several open questions in the field.
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Zhu, Shu, Makiko Watanabe, Ericka Kirkpatrick, Akilah B. Murray, Ryneth Sok, and Stephanie M. Karst. "Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency." Journal of Virology 90, no. 6 (2015): 2858–67. http://dx.doi.org/10.1128/jvi.02880-15.
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ABSTRACTHuman noroviruses are a leading cause of gastroenteritis across the globe, but the pathogenic mechanisms responsible for disease are not well established. The availability of a murine norovirus model system provides the opportunity to elucidate viral and host determinants of virulence in a natural host. For example, previous studies have revealed that the protruding domain of the murine norovirus capsid protein VP1, specifically residue 296 of VP1, regulates virulent infection. We identified a panel of nonsynonymous mutations in the open reading frame 2 (ORF2) gene encoding VP1 that arose in persistently infected mice and tested whether these mutations conferred phenotypic changes to viral replication and virulence. Consistent with previous studies, we demonstrate that a glutamic acid at position 296 results in attenuation. For the first time, we also demonstrate that a lysine at this position is sufficient to confer virulence on an otherwise attenuated murine norovirus strain. Moreover, our studies reveal a direct correlation between the efficiency of viral replication in B cells and virulence. These data are especially striking because mutations causing reduced B cell replication and attenuation had minimal effects on the ability of the virus to replicate in macrophages. Thus, norovirus infection of B cells may directly contribute to disease outcome.IMPORTANCEHuman noroviruses are a major global cause of disease, yet we know very little about their pathogenic mechanisms. The availability of a murine norovirus model system facilitates investigation of noroviruses in a natural host organism and the identification of viral and host determinants of pathogenesis. We have identified a panel of mutations arising in the viral capsid protein VP1 during persistent infection of mice. Our data reveal that the protruding domain of VP1 regulates the ability of the virus to replicate in B cells, and this directly correlates with virulence. Importantly, mutations impairing B cell infection had minimal effects on macrophage infection, revealing a potentially critical role for B cell infection in norovirus pathogenesis.
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Lohmann, Volker, Sandra Hoffmann, Ulrike Herian, Francois Penin, and Ralf Bartenschlager. "Viral and Cellular Determinants of Hepatitis C Virus RNA Replication in Cell Culture." Journal of Virology 77, no. 5 (2003): 3007–19. http://dx.doi.org/10.1128/jvi.77.5.3007-3019.2003.
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ABSTRACT Studies on the replication of hepatitis C virus (HCV) have been facilitated by the development of selectable subgenomic replicons replicating in the human hepatoma cell line Huh-7 at a surprisingly high level. Analysis of the replicon population in selected cells revealed the occurrence of cell culture-adaptive mutations that enhance RNA replication substantially. To gain a better understanding of HCV cell culture adaptation, we characterized conserved mutations identified by sequence analysis of 26 independent replicon cell clones for their effect on RNA replication. Mutations enhancing replication were found in nearly every nonstructural (NS) protein, and they could be subdivided into at least two groups by their effect on replication efficiency and cooperativity: (i) mutations in NS3 with a low impact on replication but that enhanced replication cooperatively when combined with highly adaptive mutations and (ii) mutations in NS4B, -5A, and -5B, causing a strong increase in replication but being incompatible with each other. In addition to adaptive mutations, we found that the host cell plays an equally important role for efficient RNA replication. We tested several passages of the same Huh-7 cell line and found up to 100-fold differences in their ability to support replicon amplification. These differences were not due to variations in internal ribosome entry site-dependent translation or RNA degradation. In a search for cellular factor(s) that might be responsible for the different levels of permissiveness of Huh-7 cells, we found that replication efficiency decreased with increasing amounts of transfected replicon RNA, indicating that viral RNA or proteins are cytopathic or that host cell factors in Huh-7 cells limit RNA amplification. In summary, these data show that the efficiency of HCV replication in cell culture is determined both by adaptation of the viral sequence and by the host cell itself.
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Chen, Minjie, Shuiyun Lan, Rong Ou, et al. "Genomic and biological characterization of aggressive and docile strains of lymphocytic choriomeningitis virus rescued from a plasmid-based reverse-genetics system." Journal of General Virology 89, no. 6 (2008): 1421–33. http://dx.doi.org/10.1099/vir.0.83464-0.
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Arenaviruses include several causative agents of haemorrhagic fever disease in humans. In addition, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a superb model for the study of virus–host interactions, including the basis of viral persistence and associated diseases. There is little understanding about the molecular mechanisms concerning the regulation and specific role of viral proteins in modulating arenavirus–host cell interactions either associated with an acute or persistent infection, and associated disease. Here, we report the genomic and biological characterization of LCMV strains ‘Docile’ (persistent) and ‘Aggressive’ (not persistent) recovered from cloned cDNA via reverse genetics. Our results confirmed that the cloned viruses accurately recreated the in vivo phenotypes associated with the corresponding natural Docile and Aggressive viral isolates. In addition, we provide evidence that the ability of the Docile strain to persist is determined by the nature of both S and L RNA segments. Thus, our findings provide the foundation for studies aimed at gaining a detailed understanding of viral determinants of LCMV persistence in its natural host, which may aid in the development of vaccines to prevent or treat the diseases caused by arenaviruses in humans.
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Pellaers, Eline, Anayat Bhat, Frauke Christ, and Zeger Debyser. "Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection." Viruses 15, no. 1 (2022): 32. http://dx.doi.org/10.3390/v15010032.
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To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, overwhelming evidence from cell culture, animal experiments and clinical data suggests that integration sites are important for retroviral replication, oncogenesis and/or latency. In this review, we will summarize the increasing knowledge of the mechanisms underlying the integration site selection of the gammaretrovirus MLV and the lentivirus HIV-1. We will discuss how host factors of the integration site selection of retroviruses may steer the development of safer viral vectors for gene therapy. Next, we will discuss how altering the integration site preference of HIV-1 using small molecules could lead to a cure for HIV-1 infection.