The Experts below are selected from a list of 240 Experts worldwide ranked by ideXlab platform
Dominik Wodarz - One of the best experts on this subject based on the ideXlab platform.
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Quantifying the dynamics of viral recombination during Free Virus and cell-to-cell transmission in HIV-1 infection
Virus Evolution, 2021Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik Wodarz, Josephine Garcia, Hongtao Zhang, David N. LevyAbstract:Abstract Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of Virus transmission in the cell population. HIV-1 can spread by Free Virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple Viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter Viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. Assuming a fixed basic reproductive ratio of the Virus (independent of transmission pathway), we find that recombinant evolution is fastest if Virus spread is driven only by cell-to-cell transmission, and slows down if both transmission pathways operate. Recombinant evolution is slowest if all Virus spread occurs through Free Virus transmission. This is due to cell-to-cell transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different Virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 Viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to Free Virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution.
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Quantifying the dynamics of viral recombination during Free Virus and cell-to-cell transmission in HIV-1 infection
2020Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik Wodarz, Josephine Garcia, David N. LevyAbstract:Abstract Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of Virus transmission in the cell population. HIV-1 can spread by Free Virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple Viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter Viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. We find that recombinant evolution is fastest if only synaptic transmission operates, and that the addition of Free Virus transmission reduces the number of recombinants at a given infected cell population size. This is due to synaptic transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different Virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 Viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to Free Virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution within patients.
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Effect of synaptic cell-to-cell transmission and recombination on the evolution of double mutants in HIV
Journal of the Royal Society Interface, 2020Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik WodarzAbstract:Recombination in HIV infection can impact Virus evolution in vivo in complex ways, as has been shown both experimentally and mathematically. The effect of Free Virus versus synaptic, cell-to-cell transmission on the evolution of double mutants, however, has not been investigated. Here, we do so by using a stochastic agent-based model. Consistent with data, we assume spatial constraints for synaptic but not for Free-Virus transmission. Two important effects of the viral spread mode are observed: (i) for disadvantageous mutants, synaptic transmission protects against detrimental effects of recombination on double mutant persistence. Under Free Virus transmission, recombination increases double mutant levels for negative epistasis, but reduces them for positive epistasis. This reduction for positive epistasis is much diminished under predominantly synaptic transmission, and recombination can, in fact, lead to increased mutant levels. (ii) The mode of Virus spread also directly influences the evolutionary fate of double mutants. For disadvantageous mutants, double mutant production is the predominant driving force, and hence synaptic transmission leads to highest double mutant levels due to increased transmission efficiency. For advantageous mutants, double mutant spread is the most important force, and hence Free Virus transmission leads to fastest invasion due to better mixing. For neutral mutants, both production and spread of double mutants are important, and hence an optimal mixture of Free Virus and synaptic transmission maximizes double mutant fractions. Therefore, both Free Virus and synaptic transmission can enhance or delay double mutant evolution. Implications for drug resistance in HIV are discussed.
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Relative contribution of Free-Virus and synaptic transmission to the spread of HIV-1 through target cell populations
Biology letters, 2012Co-Authors: Natalia L. Komarova, Daniela Anghelina, Igor Voznesensky, Benjamin Trinité, David N. Levy, Dominik WodarzAbstract:Human immunodeficiency Virus can spread through target cells by transmission of cell-Free Virus or directly from cell-to-cell via formation of virological synapses. Although cell-to-cell transmission has been described as much more efficient than cell-Free infection, the relative contribution of the two transmission pathways to Virus growth during multiple rounds of replication remains poorly defined. Here, we fit a mathematical model to previously published and newly generated in vitro data, and determine that Free-Virus and synaptic transmission contribute approximately equally to the growth of the Virus population.
Charles Grose - One of the best experts on this subject based on the ideXlab platform.
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Variable Effects of Autophagy Induction by Trehalose on HerpesViruses Depending on Conditions of Infection.
The Yale journal of biology and medicine, 2017Co-Authors: Jeffery L. Meier, Charles GroseAbstract:Trehalose is a non-reducing sugar formed from two glucose units. Trehalose induces abundant autophagy in cultured cells and also reduces the rate of aggregation of the huntingtin protein in the animal model of Huntington disease, a chronic neurological disease in humans. The mechanism of this effect on autophagy is now known to be caused by starvation secondary to inhibition of a family of glucose transporters known as the solute carrier 2 or the glucose transporter family. Variable effects of trehalose treatment have been observed during infections with two herpesViruses-human cytomegaloVirus and varicella-zoster Virus. The reasons for differing results have now been delineated. These differences are caused by two variables in conditions of infection: timing of addition of trehalose and type of inoculum (cell-Free Virus vs. infected cells). When monolayers pretreated with trehalose were inoculated with cell-Free Virus, there was a decline in Virus spread by as much as 93 percent when compared with untreated monolayers. However, when monolayers were inoculated with infected cells rather than cell-Free Virus, there was no decline in Virus spread. These results demonstrated that the effect of trehalose was limited to monolayers that were starved when inoculated with cell-Free Virus. In contrast, sufficient Virus was already present in infected cell inocula so as to minimize any inhibitory effect of a starved monolayer. These results also showed that trehalose did not specifically inhibit a herpesVirus; rather, addition of trehalose to cell culture media altered the intracellular environment.
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autophagic flux without a block differentiates varicella zoster Virus infection from herpes simplex Virus infection
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Erin M Buckingham, John E Carpenter, Wallen Jackson, Leigh Zerboni, Ann M Arvin, Charles GroseAbstract:Autophagy is a process by which misfolded and damaged proteins are sequestered into autophagosomes, before degradation in and recycling from lysosomes. We have extensively studied the role of autophagy in varicella-zoster Virus (VZV) infection, and have observed that vesicular cells are filled with >100 autophagosomes that are easily detectable after immunolabeling for the LC3 protein. To confirm our hypothesis that increased autophagosome formation was not secondary to a block, we examined all conditions of VZV infection as well as carrying out two assessments of autophagic flux. We first investigated autophagy in human skin xenografts in the severe combined immunodeficiency (SCID) mouse model of VZV pathogenesis, and observed that autophagosomes were abundant in infected human skin tissues. We next investigated autophagy following infection with sonically prepared cell-Free Virus in cultured cells. Under these conditions, autophagy was detected in a majority of infected cells, but was much less than that seen after an infected-cell inoculum. In other words, inoculation with lower-titered cell-Free Virus did not reflect the level of stress to the VZV-infected cell that was seen after inoculation of human skin in the SCID mouse model or monolayers with higher-titered infected cells. Finally, we investigated VZV-induced autophagic flux by two different methods (radiolabeling proteins and a dual-colored LC3 plasmid); both showed no evidence of a block in autophagy. Overall, therefore, autophagy within a VZV-infected cell was remarkably different from autophagy within an HSV-infected cell, whose genome contains two modifiers of autophagy, ICP34.5 and US11, not present in VZV.
Natalia L. Komarova - One of the best experts on this subject based on the ideXlab platform.
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Quantifying the dynamics of viral recombination during Free Virus and cell-to-cell transmission in HIV-1 infection
Virus Evolution, 2021Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik Wodarz, Josephine Garcia, Hongtao Zhang, David N. LevyAbstract:Abstract Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of Virus transmission in the cell population. HIV-1 can spread by Free Virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple Viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter Viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. Assuming a fixed basic reproductive ratio of the Virus (independent of transmission pathway), we find that recombinant evolution is fastest if Virus spread is driven only by cell-to-cell transmission, and slows down if both transmission pathways operate. Recombinant evolution is slowest if all Virus spread occurs through Free Virus transmission. This is due to cell-to-cell transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different Virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 Viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to Free Virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution.
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Quantifying the dynamics of viral recombination during Free Virus and cell-to-cell transmission in HIV-1 infection
2020Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik Wodarz, Josephine Garcia, David N. LevyAbstract:Abstract Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of Virus transmission in the cell population. HIV-1 can spread by Free Virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple Viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter Viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. We find that recombinant evolution is fastest if only synaptic transmission operates, and that the addition of Free Virus transmission reduces the number of recombinants at a given infected cell population size. This is due to synaptic transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different Virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 Viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to Free Virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution within patients.
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Effect of synaptic cell-to-cell transmission and recombination on the evolution of double mutants in HIV
Journal of the Royal Society Interface, 2020Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik WodarzAbstract:Recombination in HIV infection can impact Virus evolution in vivo in complex ways, as has been shown both experimentally and mathematically. The effect of Free Virus versus synaptic, cell-to-cell transmission on the evolution of double mutants, however, has not been investigated. Here, we do so by using a stochastic agent-based model. Consistent with data, we assume spatial constraints for synaptic but not for Free-Virus transmission. Two important effects of the viral spread mode are observed: (i) for disadvantageous mutants, synaptic transmission protects against detrimental effects of recombination on double mutant persistence. Under Free Virus transmission, recombination increases double mutant levels for negative epistasis, but reduces them for positive epistasis. This reduction for positive epistasis is much diminished under predominantly synaptic transmission, and recombination can, in fact, lead to increased mutant levels. (ii) The mode of Virus spread also directly influences the evolutionary fate of double mutants. For disadvantageous mutants, double mutant production is the predominant driving force, and hence synaptic transmission leads to highest double mutant levels due to increased transmission efficiency. For advantageous mutants, double mutant spread is the most important force, and hence Free Virus transmission leads to fastest invasion due to better mixing. For neutral mutants, both production and spread of double mutants are important, and hence an optimal mixture of Free Virus and synaptic transmission maximizes double mutant fractions. Therefore, both Free Virus and synaptic transmission can enhance or delay double mutant evolution. Implications for drug resistance in HIV are discussed.
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Relative contribution of Free-Virus and synaptic transmission to the spread of HIV-1 through target cell populations
Biology letters, 2012Co-Authors: Natalia L. Komarova, Daniela Anghelina, Igor Voznesensky, Benjamin Trinité, David N. Levy, Dominik WodarzAbstract:Human immunodeficiency Virus can spread through target cells by transmission of cell-Free Virus or directly from cell-to-cell via formation of virological synapses. Although cell-to-cell transmission has been described as much more efficient than cell-Free infection, the relative contribution of the two transmission pathways to Virus growth during multiple rounds of replication remains poorly defined. Here, we fit a mathematical model to previously published and newly generated in vitro data, and determine that Free-Virus and synaptic transmission contribute approximately equally to the growth of the Virus population.
Jesse Kreger - One of the best experts on this subject based on the ideXlab platform.
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Quantifying the dynamics of viral recombination during Free Virus and cell-to-cell transmission in HIV-1 infection
Virus Evolution, 2021Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik Wodarz, Josephine Garcia, Hongtao Zhang, David N. LevyAbstract:Abstract Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of Virus transmission in the cell population. HIV-1 can spread by Free Virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple Viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter Viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. Assuming a fixed basic reproductive ratio of the Virus (independent of transmission pathway), we find that recombinant evolution is fastest if Virus spread is driven only by cell-to-cell transmission, and slows down if both transmission pathways operate. Recombinant evolution is slowest if all Virus spread occurs through Free Virus transmission. This is due to cell-to-cell transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different Virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 Viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to Free Virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution.
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Quantifying the dynamics of viral recombination during Free Virus and cell-to-cell transmission in HIV-1 infection
2020Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik Wodarz, Josephine Garcia, David N. LevyAbstract:Abstract Recombination has been shown to contribute to HIV-1 evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of Virus transmission in the cell population. HIV-1 can spread by Free Virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple Viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter Viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. We find that recombinant evolution is fastest if only synaptic transmission operates, and that the addition of Free Virus transmission reduces the number of recombinants at a given infected cell population size. This is due to synaptic transmission (i) increasing infection multiplicity, (ii) promoting the co-transmission of different Virus strains from cell to cell, and (iii) increasing the rate at which point mutations are generated as a result of more reverse transcription events. This work further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of 3 Viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to Free Virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV-evolution within patients.
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Effect of synaptic cell-to-cell transmission and recombination on the evolution of double mutants in HIV
Journal of the Royal Society Interface, 2020Co-Authors: Jesse Kreger, Natalia L. Komarova, Dominik WodarzAbstract:Recombination in HIV infection can impact Virus evolution in vivo in complex ways, as has been shown both experimentally and mathematically. The effect of Free Virus versus synaptic, cell-to-cell transmission on the evolution of double mutants, however, has not been investigated. Here, we do so by using a stochastic agent-based model. Consistent with data, we assume spatial constraints for synaptic but not for Free-Virus transmission. Two important effects of the viral spread mode are observed: (i) for disadvantageous mutants, synaptic transmission protects against detrimental effects of recombination on double mutant persistence. Under Free Virus transmission, recombination increases double mutant levels for negative epistasis, but reduces them for positive epistasis. This reduction for positive epistasis is much diminished under predominantly synaptic transmission, and recombination can, in fact, lead to increased mutant levels. (ii) The mode of Virus spread also directly influences the evolutionary fate of double mutants. For disadvantageous mutants, double mutant production is the predominant driving force, and hence synaptic transmission leads to highest double mutant levels due to increased transmission efficiency. For advantageous mutants, double mutant spread is the most important force, and hence Free Virus transmission leads to fastest invasion due to better mixing. For neutral mutants, both production and spread of double mutants are important, and hence an optimal mixture of Free Virus and synaptic transmission maximizes double mutant fractions. Therefore, both Free Virus and synaptic transmission can enhance or delay double mutant evolution. Implications for drug resistance in HIV are discussed.
Seiji Kageyama - One of the best experts on this subject based on the ideXlab platform.
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Functions of purified gB, gE:gI, and gH:gL, and their sialyl residues in varicella-zoster Virus infection
Archives of virology, 1997Co-Authors: K Shiraki, Hitoshi Sato, Jun-ichi Yamamura, T. Yokoyama, T. Hasegawa, T. Okuno, Masahiko Kurokawa, Seiji KageyamaAbstract:Varicella-zoster Virus glycoproteins were purified by using monoclonal antibodies and analyzed for their effects on cell-Free Virus infection. Preinfection treatment of cells with gH:gL reduced the infection efficiency and increased the number of unadsorbed Virus. Postinfection treatment of cells with gB increased the infection efficiency, but that with gE:gI reduced it. Treatment of gE:gI and gH:gL with neuraminidase (NA) abolished their inhibitory activity and the plaque formation was enhanced by NA treatment of glycoproteins and cells. Glycoproteins exhibited their diverse activities despite their common role in viral penetration, and sialyl residues were responsible for their function in cell-Free Virus infection.
