Modeling Viral Spread.

The way in which a viral infection spreads within a host is a complex process that is not well understood. Different viruses, such as human immunodeficiency virus type 1 and hepatitis C virus, have evolved different strategies, including direct cell-to-cell transmission and cell-free transmission, to spread within a host. To what extent these two modes of transmission are exploited in vivo is still unknown. Mathematical modeling has been an essential tool to get a better systematic and quantitative understanding of viral processes that are difficult to discern through strictly experimental approaches. In this review, we discuss recent attempts that combine experimental data and mathematical modeling in order to determine and quantify viral transmission modes. We also discuss the current challenges for a systems-level understanding of viral spread, and we highlight the promises and challenges that novel experimental techniques and data will bring to the field.

[1]  John Yin,et al.  Visualizing infection spread: Dual‐color fluorescent reporting of virus–host interactions , 2014, Biotechnology and bioengineering.

[2]  D. McDonald,et al.  Visualization of the intracellular behavior of HIV in living cells , 2002, The Journal of cell biology.

[3]  Alan S. Perelson,et al.  Agent-based modeling of host–pathogen systems: The successes and challenges , 2008, Information Sciences.

[4]  Lawrence Corey,et al.  Dynamics of hepatitis C virus replication in human liver. , 2003, The American journal of pathology.

[5]  O. Schwartz,et al.  Inefficient Human Immunodeficiency Virus Replication in Mobile Lymphocytes , 2006, Journal of Virology.

[6]  Sebastian Bonhoeffer,et al.  Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis , 1999, The Lancet.

[7]  S. Guadagnini,et al.  Simultaneous Cell-to-Cell Transmission of Human Immunodeficiency Virus to Multiple Targets through Polysynapses , 2009, Journal of Virology.

[8]  Sebastian Bonhoeffer,et al.  Spatial models of virus-immune dynamics. , 2005, Journal of theoretical biology.

[9]  Alan S. Perelson,et al.  Modelling hepatitis C therapy—predicting effects of treatment , 2015, Nature Reviews Gastroenterology &Hepatology.

[10]  K. Shimotohno,et al.  Hepatitis C virus utilizes VLDLR as a novel entry pathway , 2015, Proceedings of the National Academy of Sciences.

[11]  Alan S. Perelson,et al.  Multiplicity of Human Immunodeficiency Virus Infections in Lymphoid Tissue , 2004, Journal of Virology.

[12]  Karl Rohr,et al.  Visualizing fusion of pseudotyped HIV-1 particles in real time by live cell microscopy , 2009, Retrovirology.

[13]  Frank Y. S. Chuang,et al.  Quantitative 3D Video Microscopy of HIV Transfer Across T Cell Virological Synapses , 2009, Science.

[14]  Jean Gruenberg,et al.  Nef-Induced CD4 Degradation A Diacidic-Based Motif in Nef Functions as a Lysosomal Targeting Signal through the Binding of β-COP in Endosomes , 1999, Cell.

[15]  L. Richardson.  Viral Cell-to-Cell Transmission—Why Less Is More , 2015, PLoS biology.

[16]  Walther Mothes,et al.  HIV cell-to-cell transmission: effects on pathogenesis and antiretroviral therapy. , 2015, Trends in microbiology.

[17]  N. Pochet,et al.  A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses , 2016, Hepatology.

[18]  Alan S. Perelson,et al.  Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-α Therapy , 1998 .

[19]  Q. Sattentau,et al.  Adhesion Molecule Interactions Facilitate Human Immunodeficiency Virus Type 1-Induced Virological Synapse Formation between T Cells , 2007, Journal of Virology.

[20]  K Inaba,et al.  Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. , 1992, Science.

[21]  A. Perelson,et al.  HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time , 1996, Science.

[22]  Michael Loran Dustin,et al.  HIV-1 Virological Synapse is not Simply a Copycat of the Immunological Synapse , 2010, Viruses.

[23]  H. Kishino,et al.  Viruses Roll the Dice: The Stochastic Behavior of Viral Genome Molecules Accelerates Viral Adaptation at the Cell and Tissue Levels , 2015, PLoS biology.

[24]  George Towfic,et al.  Effect of spatial distribution of T-Cells and HIV load on HIV progression , 2008, Bioinform..

[25]  A. Trkola,et al.  Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies , 2012, PLoS pathogens.

[26]  John Samuel,et al.  A simple cellular automaton model for influenza A viral infections. , 2004, Journal of theoretical biology.

[27]  D. McDonald,et al.  Recruitment of HIV and Its Receptors to Dendritic Cell-T Cell Junctions , 2003, Science.

[28]  Thomas F. Baumert,et al.  Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission , 2010, Journal of Virology.

[29]  Ralf Bartenschlager,et al.  Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81 , 2007, Hepatology.

[30]  E. Voigt,et al.  Rapid induction and persistence of paracrine-induced cellular antiviral states arrest viral infection spread in A549 cells. , 2016, Virology.

[31]  Q. Sattentau,et al.  Multiple proviral integration events after virological synapse-mediated HIV-1 spread. , 2013, Virology.

[32]  Alan S. Perelson,et al.  Mathematical Modeling of Subgenomic Hepatitis C Virus Replication in Huh-7 Cells , 2006, Journal of Virology.

[33]  W. Greene,et al.  Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells. , 2015, Cell reports.

[34]  Ruy M Ribeiro,et al.  Modeling the within-host dynamics of HIV infection , 2013, BMC Biology.

[35]  Anushree Chatterjee,et al.  Mathematical modelling of HCV infection: what can it teach us in the era of direct-acting antiviral agents? , 2012, Antiviral therapy.

[36]  Gianguido C. Cianci,et al.  Visualization of HIV-1 Interactions with Penile and Foreskin Epithelia: Clues for Female-to-Male HIV Transmission , 2015, PLoS pathogens.

[37]  Alan S. Perelson,et al.  Quantifying the Diversification of Hepatitis C Virus (HCV) during Primary Infection: Estimates of the In Vivo Mutation Rate , 2012, PLoS pathogens.

[38]  A. Perelson.  Modelling viral and immune system dynamics , 2002, Nature Reviews Immunology.

[39]  A. Cereseto,et al.  Single-Cell Imaging of HIV-1 Provirus (SCIP) , 2013, Proceedings of the National Academy of Sciences.

[40]  M. Houghton,et al.  Binding of hepatitis C virus to CD81. , 1998, Science.

[41]  M. Nowak,et al.  Virus dynamics: Mathematical principles of immunology and virology , 2001 .

[42]  Wei Shao,et al.  Majority of CD4+ T cells from peripheral blood of HIV-1–infected individuals contain only one HIV DNA molecule , 2011, Proceedings of the National Academy of Sciences.

[43]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[44]  Ian Williams,et al.  Hybrid Spreading Mechanisms and T Cell Activation Shape the Dynamics of HIV-1 Infection , 2015, PLoS Comput. Biol..

[45]  S. Frank.  Within-host spatial dynamics of viruses and defective interfering particles. , 2000, Journal of theoretical biology.

[46]  Jianping Liu,et al.  Human Immunodeficiency Virus Type 1 Envelope gp120 Induces a Stop Signal and Virological Synapse Formation in Noninfected CD4+ T Cells , 2008, Journal of Virology.

[47]  Alan S. Perelson,et al.  Viral kinetic modeling: state of the art , 2014, Journal of Pharmacokinetics and Pharmacodynamics.

[48]  Dominik Wodarz,et al.  Virus dynamics in the presence of synaptic transmission. , 2013, Mathematical biosciences.

[49]  Harel Dahari,et al.  Understanding silibinin's modes of action against HCV using viral kinetic modeling. , 2012, Journal of hepatology.

[50]  Ron Milo,et al.  Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy , 2011, Nature.

[51]  K. Rohr,et al.  Live Cell Analysis and Mathematical Modeling Identify Determinants of Attenuation of Dengue Virus 2’-O-Methylation Mutant , 2015, PLoS pathogens.

[52]  R. Doms,et al.  Molecular mechanisms of HIV entry. , 2012, Advances in experimental medicine and biology.

[53]  W. Hübner,et al.  Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses , 2007, Journal of Virology.

[54]  Charles M. Rice,et al.  Human occludin is a hepatitis C virus entry factor required for infection of mouse cells , 2009, Nature.

[55]  Nathan M. Sherer,et al.  Virus Cell-to-Cell Transmission , 2010, Journal of Virology.

[56]  Q. Sattentau,et al.  Avoiding the void: cell-to-cell spread of human viruses , 2008, Nature Reviews Microbiology.

[57]  Bryan T Grenfell,et al.  Modelling dynamics of the type I interferon response to in vitro viral infection , 2006, Journal of The Royal Society Interface.

[58]  Natalia L. Komarova,et al.  Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs , 2013, Scientific Reports.

[59]  Alan S. Perelson,et al.  Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus , 2010, Science Translational Medicine.

[60]  Alan S. Perelson,et al.  Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes , 2014, PLoS Comput. Biol..

[61]  Benjamin K. Chen,et al.  Unique Features of HIV-1 Spread through T Cell Virological Synapses , 2014, PLoS pathogens.

[62]  A. Perelson,et al.  Modelling how ribavirin improves interferon response rates in hepatitis C virus infection , 2004, Nature.

[63]  A. Perelson.  Mathematical Modeling: Solving Equations to Measure Viral Diseases—Math Rules , 2016 .

[64]  C. Seeger,et al.  Focal Distribution of Hepatitis C Virus RNA in Infected Livers , 2009, PloS one.

[65]  Clare Jolly,et al.  HIV-1 Cell to Cell Transfer across an Env-induced, Actin-dependent Synapse , 2004, The Journal of experimental medicine.

[66]  Ralf Bartenschlager,et al.  Quantitative Analysis of the Hepatitis C Virus Replication Complex , 2005, Journal of Virology.

[67]  James B. Munro,et al.  Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission , 2014, PLoS pathogens.

[68]  Andrew D. Luster,et al.  HIV-infected T cells are migratory vehicles for viral dissemination , 2012, Nature.

[69]  S. Uprichard,et al.  Identification of transferrin receptor 1 as a hepatitis C virus entry factor , 2013, Proceedings of the National Academy of Sciences.

[70]  Jeremie Guedj,et al.  Analysis of Hepatitis C Viral Kinetics during Administration of Two Nucleotide Analogues: Sofosbuvir (Gs-7977) and Gs-0938 , 2014, Antiviral therapy.

[71]  Kazuyuki Aihara,et al.  Cell-to-cell infection by HIV contributes over half of virus infection , 2015, eLife.

[72]  G. Randall,et al.  Spatiotemporal Analysis of Hepatitis C Virus Infection , 2015, PLoS pathogens.

[73]  F. Chisari,et al.  Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver , 2014, Hepatology.

[74]  Wenhui Li,et al.  Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus , 2012, eLife.

[75]  Johannes P. Schlöder,et al.  Replication Vesicles are Load- and Choke-Points in the Hepatitis C Virus Lifecycle , 2013, PLoS pathogens.

[76]  Libin Rong,et al.  Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life , 2013, Proceedings of the National Academy of Sciences.

[77]  Tuya Shilagard,et al.  Visualizing hepatitis C virus infections in human liver by two-photon microscopy. , 2009, Gastroenterology.

[78]  Dominik Wodarz,et al.  Multiploid Inheritance of HIV-1 during Cell-to-Cell Infection , 2011, Journal of Virology.

[79]  Bing Li,et al.  Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study. , 2016, The lancet. Gastroenterology & hepatology.

[80]  G. Bocharov,et al.  Recombination: Multiply infected spleen cells in HIV patients , 2002, Nature.

[81]  A. Perelson,et al.  Quantification of Hepatitis C Virus Cell-to-Cell Spread Using a Stochastic Modeling Approach , 2015, Journal of Virology.

[82]  Frederik Graw,et al.  Use of laser capture microdissection to map hepatitis C virus-positive hepatocytes in human liver. , 2013, Gastroenterology.

[83]  Naina Barretto,et al.  Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread , 2014, Journal of Virology.

[84]  Andrea Imle,et al.  Adding new dimensions: towards an integrative understanding of HIV-1 spread , 2014, Nature Reviews Microbiology.

[85]  A. Trkola,et al.  The HIV-1 Entry Process: A Stoichiometric View. , 2015, Trends in microbiology.

[86]  John A. G. Briggs,et al.  Virological Synapse-Mediated Spread of Human Immunodeficiency Virus Type 1 between T Cells Is Sensitive to Entry Inhibition , 2010, Journal of Virology.

[87]  Charles M. Rice,et al.  Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry , 2007, Nature.

[88]  Ellen A. Robey,et al.  Dynamic imaging of host–pathogen interactions in vivo , 2010, Nature Reviews Immunology.

[89]  F. Chisari,et al.  Plasmacytoid dendritic cells sense hepatitis C virus–infected cells, produce interferon, and inhibit infection , 2010, Proceedings of the National Academy of Sciences.

[90]  Alan S Perelson,et al.  Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues , 2014, Proceedings of the National Academy of Sciences.

[91]  Trevor Bedford,et al.  Persistent HIV-1 replication maintains the tissue reservoir during therapy , 2015, Nature.

[92]  R. M. Zorzenon dos Santos,et al.  Dynamics of HIV infection: a cellular automata approach. , 2001, Physical review letters.

[93]  M. Imamura,et al.  Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor , 2011, Nature Medicine.

[94]  D. Richman,et al.  Spatiotemporal dynamics of HIV propagation. , 2002, Journal of theoretical biology.

[95]  Natalia L. Komarova,et al.  Effect of Synaptic Transmission on Viral Fitness in HIV Infection , 2012, PloS one.

[96]  L. Kaderali,et al.  Identification of type I and type II interferon‐induced effectors controlling hepatitis C virus replication , 2012, Hepatology.