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Paul Jolicoeur - One of the best experts on this subject based on the ideXlab platform.
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Establishment of MAIDS-Defective Virus-infected B cell lines and their characterization.
Virology, 1998Co-Authors: Steven J. Klein, Carole Simard, Paul JolicoeurAbstract:Abstract Mice inoculated with the murine AIDS (MAIDS)-Defective Virus develop severe B and T cell dysfunctions. The primary event in the development of this disease is the infection and polyclonal expansion of the target cells of this Defective Virus, which have been reported to belong to the B cell lineage. To further study the central role that these cells play in the development of MAIDS, we attempted to establish MAIDS-Defective Virus-infected B cell lines in vitro. We succeeded in establishing two cell lines, SD1 and CSTB5, from the enlarged organs of C57BL/6 mice inoculated with helper-free stocks of the MAIDS-Defective Virus. Both cell lines are not transplantable in syngeneic C57BL/6 mice or in nude or CD8 −/− mice and are apparently not malignant. They both belong to the B lineage, as their immunoglobulin (Ig) genes, but not the T cell receptor (TcR) β locus, are rearranged, suggesting that they are relatively mature B cells. However, analysis of cell surface marker expression by FACS revealed a surface phenotype similar to that of pre-B cells (MHC I + , MHC II + , B7.2 + , sIgM − , sIgG − , κ − , B220 − , CD5 − , Thy1.2 − , TcR − , CD3 − , CD4 − , CD8 − , Mac-1 − , 33D1 − ). Additionally, the CSTB5 cells express CD40 and the SD1 cells express CD43. Both cell lines contain the MAIDS-Defective proVirus and express the expected 4.2-kb viral RNA and the corresponding Pr60 gag protein. The CSTB5 cells are nonproducer, while the SD1 cell line produces what appears to be an endogenous MuLV. The phenotype of these cell lines is very similar to what is known about the target B cells of this Virus in vivo. These new established cell lines are likely to be useful in elucidating the mechanism(s) by which the MAIDS-Defective Virus causes its target B cells to proliferate and induce T cell anergy in infected animals.
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Studies of the susceptibility of nude, CD4 knockout, and SCID mutant mice to the disease induced by the murine AIDS Defective Virus.
Journal of virology, 1997Co-Authors: Carole Simard, S J Klein, Tak W. Mak, Paul JolicoeurAbstract:Murine AIDS (MAIDS) is induced by a Defective retroVirus that infects lymphocyte cells of the B lineage. To determine whether functional T cells are required for the infection of B cells, T-cell-deficient mice (nude, CD4 knockout, and SCII)) were infected with helper-free stocks of the MAIDS Defective Virus. Infection of B cells was monitored by Northern blot analysis and in situ hybridization. The C57BL/6 nude mice contained clusters of infected B cells, but less so than did the euthymic mice. In contrast, the (C57BL/6 x BALB/c)F1 nude mice harbored more infected B cells than did their euthymic littermates when maintained in a pathogen-free environment. Clusters of infected B cells were also detected in the MAIDS Virus-infected CD4-/- knockout mice despite the total absence of CD4+ T cells in these mice. However, infected cells were not detected in SCID mice (deficient in mature T and B cells) inoculated with the same Virus, indicating that precursor B cells are not a target of the Virus in the absence of mature CD4+ T cells. These data confirm that the primary event in the development of MAIDS is the infection of relatively mature peripheral B cells and that CD4+ T cells are required to promote the expansion of these infected B cells.
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Evidence that the murine AIDS Defective Virus does not encode a superantigen.
Journal of virology, 1996Co-Authors: L Doyon, C Simard, R P Sekaly, Paul JolicoeurAbstract:The T-cell receptor repertoire was analyzed in C57BL/6 mice upon infection with helper-free stocks of the pathogenic murine AIDS (MAIDS) Defective Virus in order to demonstrate if, as previously reported, this Virus encodes a superantigen. A polyclonal T-cell stimulation involving T cells expressing multiple V beta subsets occurred within the first week of infection, while late in the disease we could note only a 50% deletion of V beta 5 CD8+ cells. Transfection of the MAIDS Virus genomic DNA into fibroblasts and B cells expressing major histocompatibility complex class II molecules failed to show any stimulation of cells expressing the specific V beta (V beta 5) previously reported to respond to MAIDS Virus-infected cells. In addition, mice lacking V beta 5 cells did not show any significant decrease in susceptibility to the disease compared with mice expressing V beta 5 and bred on the same genetic background. Our in vivo and in vitro results fail to demonstrate a role for a superantigen encoded by the MAIDS Defective viral genome in the pathogenesis of MAIDS.
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Establishment of leukemic T-cell lines from mice inoculated with the MAIDS Defective Virus.
Virology, 1995Co-Authors: Carole Simard, Ming Huang, Paul JolicoeurAbstract:Mice inoculated with replication-competent stocks of the murine acquired immunodeficiency syndrome (MAIDS) Virus are severely immunocompromised and proned to the development of T- and B-cell lymphomas. We have studied the development of T-cell lymphomas in C57BL/6 and RF/J mice inoculated with helper-free stocks of the MAIDS Defective Virus. We observed the expansion of T cell clones (detected by TCR gene rearrangements and by transplantation) only rarely in diseased C57BL/6 mice and slightly more frequently in RF/J mice. We succeeded in establishing four transplantable T cell tumors and malignant cell lines. The three cell lines from RF/J mice were immature T-cells (Thy-1+, CD3-, CD4+, CD8+, Mac-1+), while the line from the C57BL/6 mouse had the phenotype of mature T-cells (Thy-1+, CD3+, CD4+, CD8-). All lines were Virus-producers despite the fact that helper-free stocks of the Virus were inoculated. These helper MuLVs most likely originated from endogenous MuLV sequences. Also, the Defective viral genome was clearly detectable in one cell line and was rearranged in two other lines. These established cell lines may be useful to determine whether they share some of the characteristics of the anergic T-cells in vivo and to study the role of the MAIDS Defective Virus in T cell transformation.
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Mutational analysis of the murine AIDS-Defective viral genome reveals a high reversion rate in vivo and a requirement for an intact Pr60gag protein for efficient induction of disease.
Journal of virology, 1995Co-Authors: Ming Huang, Zaher Hanna, Paul JolicoeurAbstract:Pr60gag appears to be the only protein encoded by the murine AIDS (MAIDS)-Defective Virus. To study the role of Pr60gag or some other sequences of the viral genome in the pathogenicity of the Virus, we have generated mutants of the Defective viral genome. These mutant Defective Viruses, prepared as helper-free stocks, were inoculated into susceptible C57BL/6 mice. Mutant Du5H-A Virus, which had a stop codon within gag MA(p15), did not induce target cell proliferation or MAIDS. Mutants Du5H-B and -C encoded truncated Pr60gag proteins containing, respectively, MA(p15)-p12 or MA(p15)-p12 and part of CA(p30). These mutants showed a very limited capacity to induce early cell expansion and were poorly pathogenic. Only recombinant (revertant) Viruses were recovered from organs of diseased mice inoculated with these two mutants. Mutant Du5H-D was generated by deleting 1.4 kbp of the 3'-end sequences, outside the gag coding region. The levels of RNA and proteins made by this mutant were low. This mutant also reverting frequently but was nevertheless able to induce MAIDS at a low efficiency without reverting. Our results indicate that the Pr60gag protein is necessary and sufficient to induce MAIDS. These data also suggest that the Pr60gag protein needs to be relatively intact to be fully pathogenic. In addition, our study shows a very high reversion rate of some mutants and emphasizes the need to check for the presence of revertant (recombinant) Viruses in diseased organs when working with mutants of the MAIDS-Defective Virus.
Yong Hui Zheng - One of the best experts on this subject based on the ideXlab platform.
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Evidence for Vpr-dependent HIV-1 replication in human CD4+ CEM.NKR T-cells.
Retrovirology, 2012Co-Authors: Tao Zhou, Ying Dang, Jacob J. Baker, Jiajun Zhou, Yong Hui ZhengAbstract:Vpr is exclusively expressed in primate lentiViruses and contributes to viral replication and disease progression in vivo. HIV-1 Vpr has two major activities in vitro: arrest of cell cycle in the G2 phase (G2 arrest), and enhancement of viral replication in macrophages. Previously, we reported a potent HIV-1 restriction in the human CD4+ CEM.NKR (NKR) T cells, where wild-type (WT) HIV-1 replication was inhibited by almost 1,000-fold. From the parental NKR cells, we isolated eight clones by limiting dilution. These clones showed three levels of resistance to the WT HIV-1 infection: non-permissive (NP), semi-permissive (SP), and permissive (P). Here, we compared the replication of WT, Vif-Defective, Vpr-Defective, and Vpu-Defective Viruses in these cells. Although both WT and Vpu-Defective Viruses could replicate in the permissive and semi-permissive clones, the replication of Vif-Defective and Vpr-Defective Viruses was completely restricted. The expression of APOBEC3G (A3G) cytidine deaminase in NKR cells explains why Vif, but not Vpr, was required for HIV-1 replication. When the Vpr-Defective Virus life cycle was compared with the WT Virus life cycle in the semi-permissive cells, it was found that the Vpr-Defective Virus could enter the cell and produce virions containing properly processed Gag and Env proteins, but these virions showed much less efficiency for reverse transcription during the next-round of infection. In addition, although viral replication was restricted in the non-permissive cells, treatment with arsenic trioxide (As2O3) could completely restore WT, but not Vpr-Defective Virus replication. Moreover, disruption of Vpr binding to its cofactor DCAF1 and/or induction of G2 arrest activity did not disrupt the Vpr activity in enhancing HIV-1 replication in NKR cells. These results demonstrate that HIV-1 replication in NKR cells is Vpr-dependent. Vpr promotes HIV-1 replication from the 2nd cycle likely by overcoming a block at early stage of viral replication; and this activity does not require DCAF1 and G2 arrest. Further studies of this mechanism should provide new understanding of Vpr function in the HIV-1 life cycle.
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CEM.NKR T-cells human CD4 Evidence for Vpr-dependent HIV-1 replication in
2012Co-Authors: Tao Zhou, Ying Dang, Jacob J. Baker, Jiajun Zhou, Yong Hui ZhengAbstract:Background: Vpr is exclusively expressed in primate lentiViruses and contributes to viral replication and disease progression in vivo. HIV-1 Vpr has two major activities in vitro: arrest of cell cycle in the G2 phase (G2 arrest), and enhancement of viral replication in macrophages. Previously, we reported a potent HIV-1 restriction in the human CD4 + CEM.NKR (NKR) T cells, where wild-type (WT) HIV-1 replication was inhibited by almost 1,000-fold. From the parental NKR cells, we isolated eight clones by limiting dilution. These clones showed three levels of resistance to the WT HIV-1 infection: non-permissive (NP), semi-permissive (SP), and permissive (P). Here, we compared the replication of WT, Vif-Defective, Vpr-Defective, and Vpu-Defective Viruses in these cells. Results: Although both WT and Vpu-Defective Viruses could replicate in the permissive and semi-permissive clones, the replication of Vif-Defective and Vpr-Defective Viruses was completely restricted. The expression of APOBEC3G (A3G) cytidine deaminase in NKR cells explains why Vif, but not Vpr, was required for HIV-1 replication. When the Vpr-Defective Virus life cycle was compared with the WT Virus life cycle in the semi-permissive cells, it was found that the Vpr-Defective Virus could enter the cell and produce virions containing properly processed Gag and Env proteins, but these virions showed much less efficiency for reverse transcription during the next-round of infection. In addition, although viral replication was restricted in the non-permissive cells, treatment with arsenic trioxide (As 2
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Superinfection of a Defective Human Immunodeficiency Virus Type 1 ProVirus-Carrying T Cell Clone with vif or vpu Mutants Gives Cytopathic Virus Particles by Homologous Recombination
AIDS research and human retroviruses, 1995Co-Authors: Masahiko Kishi, Kenzo Tokunaga, Yong Hui Zheng, Mirza Khalil Bahmani, Mitsuaki Kakinuma, Meihan Nonoyama, Patrick K. Lai, Kazuyoshi IkutaAbstract:The partially CD4-expressing T cell clone, Vpr-1, which carries a latent vpr-Defective HIV-1 genome and expresses HIV-1 Nef protein only, was permissive to superinfection by HIV-1. Superinfection of Vpr-1 with vif- or vpu-Defective mutants, which were noncytopathic, reactivated the vpr-Defective Virus and led to homologous recombination and cytopathogenesis. The data provide an experimental model for homologous recombination being an important mechanism whereby HIV-1 acquires genetic heterogeneity, and when occurring among Defective Virus in vivo bestows novel biological activities and virulence.
Kevin Burrage - One of the best experts on this subject based on the ideXlab platform.
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Administration of Defective Virus Inhibits Dengue Transmission into Mosquitoes.
Viruses, 2020Co-Authors: Tarunendu Mapder, John Aaskov, Kevin BurrageAbstract:The host-vector shuttle and the bottleneck in dengue transmission is a significant aspect with regard to the study of dengue outbreaks. As mosquitoes require 100-1000 times more Virus to become infected than human, the transmission of dengue Virus from human to mosquito is a vulnerability that can be targeted to improve disease control. In order to capture the heterogeneity in the infectiousness of an infected patient population towards the mosquito population, we calibrate a population of host-to-vector Virus transmission models based on an experimentally quantified infected fraction of a mosquito population. Once the population of models is well-calibrated, we deploy a population of controls that helps to inhibit the human-to-mosquito transmission of the dengue Virus indirectly by reducing the viral load in the patient body fluid. We use an optimal bang-bang control on the administration of the Defective Virus (transmissible interfering particles (TIPs)) to symptomatic patients in the course of their febrile period and observe the dynamics in successful reduction of dengue spread into mosquitoes.
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Administration of Defective Virus via bang-bang optimal control inhibits dengue transmission
2019Co-Authors: Tarunendu Mapder, John Aaskov, Kevin BurrageAbstract:The host-vector shuttle and the bottleneck in dengue transmission is a significant aspect with regard to the study of dengue outbreaks. As mosquitoes require 100-1000 times more Virus to become infected than human, the transmission of dengue Virus from human to mosquito is a vulnerability that may be able to be targeted to improve disease control. In order to capture the heterogeneity in the infectiousness of an infected patient population towards the mosquito pool, we calibrate a population of host-to-vector Virus transmission models based on an experimentally quantified infected fraction of a mosquito population. Once the population of models is well-calibrated, we deploy a population of controls that helps to inhibit the human-to-mosquito transmission of the dengue Virus indirectly by reducing the viral load in the patient blood. We use an optimal bang-bang control on the administration of the Defective Virus (transmissible interfering particles, known as TIPs) to symptomatic patients in the course of their febrile period and observe the dynamics in successful reduction of dengue spread.
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a population of bang bang switches of Defective interfering particles makes within host dynamics of dengue Virus controllable
PLOS Computational Biology, 2019Co-Authors: Tarunendu Mapder, John Aaskov, Kevin Burrage, Samuel CliffordAbstract:The titre of Virus in a dengue patient and the duration of this viraemia has a profound effect on whether or not a mosquito will become infected when it feeds on the patient and this, in turn, is a key driver of the magnitude of a dengue outbreak. The assessment of the heterogeneity of viral dynamics in dengue-infected patients and its precise treatment are still uncertain. Infection onset, patient physiology and immune response are thought to play major roles in the development of the viral load. Research has explored the interference and spontaneous generation of Defective Virus particles, but have not examined both the antibody and Defective particles during natural infection. We explore the intrinsic variability in the within-host dynamics of viraemias for a population of patients using the method of population of models (POMs). A dataset from 208 patients is used to initially calibrate 20,000 models for the infection kinetics for each of the four dengue Virus serotypes. The calibrated POMs suggests that naturally generated Defective particles may interfere with the viraemia, but the generated Defective Virus particles are not adequate to reduce high fever and viraemia duration. The effect of adding excess Defective dengue Virus interfering particles to patients as a therapeutic is evaluated using the calibrated POMs in a bang-bang (on-off or two-step) optimal control setting. Bang-bang control is a class of binary feedback control that turns either 'ON' or 'OFF' at different time points, determined by the system feedback. Here, the bang-bang control estimates the mathematically optimal dose and duration of the intervention for each model in the POM set.
Bin Zhou - One of the best experts on this subject based on the ideXlab platform.
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Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection.
mBio, 2020Co-Authors: Chang Wang, Christian V. Forst, Tsui Wen Chou, Adam Geber, Wissam Hamou, Melissa Smith, Robert Sebra, Minghui Wang, Bin Zhang, Bin ZhouAbstract:Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts Virus-host interactions at a system level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A Virus. We observed substantial variability in viral transcription between cells, including the accumulation of Defective viral genomes (DVGs) that impact viral replication. We show (i) a correlation between DVGs and Virus-induced variation of the host transcriptional program and (ii) an association between differential inductions of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single-cell level improve our understanding of the complex Virus-host interplay during influenza Virus infection.IMPORTANCE Defective influenza Virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent Viruses. These Defective genomes are thought to modulate the disease severity and pathogenicity of an influenza Virus infection. Different Defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of Defective Virus genomes on host cell responses cannot be fully resolved at the population level, requiring single-cell transcriptional profiling. Here, we characterized Virus and host transcriptomes in individual influenza Virus-infected cells, including those of Defective Viruses that arise during influenza A Virus infection. We established an association between Defective Virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant Defective viral genome species in vitro This study demonstrates the intricate effects of Defective viral genomes on host transcriptional responses and highlights the importance of capturing host-Virus interactions at the single-cell level.
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Cell-to-cell variation in Defective Virus expression and effects on host responses during influenza Virus infection
bioRxiv, 2018Co-Authors: Chang Wang, Christian V. Forst, Tsui Wen Chou, Adam Geber, Wissam Hamou, Melissa Smith, Robert Sebra, Minghui Wang, Bin Zhang, Bin ZhouAbstract:Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single cell level and how it impacts Virus-host interactions at a systems level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A Virus. We observed substantial variability of viral transcription between cells, including the accumulation of Defective viral genomes (DVGs) that impact viral replication. We show a correlation between DVGs and viral-induced variation of the host transcriptional program and an association between differential induction of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single cell level improve our understanding of the complex Virus-host interplay during influenza infection.
Carolina B Lopez - One of the best experts on this subject based on the ideXlab platform.
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Defective viral genomes are key drivers of the Virus–host interaction
Nature Microbiology, 2019Co-Authors: Marco Vignuzzi, Carolina B LopezAbstract:This Review describes recent findings on the biogenesis and the role of Defective viral genomes during replication of RNA Viruses and discusses their impact on viral dynamics and evolution. Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replication-competent and -Defective Virus variants can provide means for adaptation, immune escape and Virus perpetuation. This Review summarizes current knowledge of the types of Defective viral genomes generated during the replication of RNA Viruses and the functions that they carry out. We highlight the universality and diversity of Defective viral genomes during infections and discuss their predicted role in maintaining a fit Virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools.
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Defective viral genomes are key drivers of the Virus host interaction
Nature microbiology, 2019Co-Authors: Marco Vignuzzi, Carolina B LopezAbstract:Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replication-competent and -Defective Virus variants can provide means for adaptation, immune escape and Virus perpetuation. This Review summarizes current knowledge of the types of Defective viral genomes generated during the replication of RNA Viruses and the functions that they carry out. We highlight the universality and diversity of Defective viral genomes during infections and discuss their predicted role in maintaining a fit Virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools.
