title: Quantifying the Sensitivity of HIV-1 Viral Entry to Receptor and Coreceptor Expression.
abstract: Infection by many viruses begins with fusion of viral and cellular lipid membranes, followed by entry of viral contents into the target cell and ultimately, after many biochemical steps, integration of viral DNA into that of the host cell. The early steps of membrane fusion and viral capsid entry are mediated by adsorption to the cell surface, and receptor and coreceptor binding. HIV-1 specifically targets CD4+ helper T-cells of the human immune system and binds to the receptor CD4 and coreceptor CCR5 before fusion is initiated. Previous experiments have been performed using a cell line (293-Affinofile) in which the expressions of CD4 and CCR5 concentration were independently controlled. After exposure to HIV-1 of various strains, the resulting infectivity was measured through the fraction of infected cells. To design and evaluate the effectiveness of drug therapies that target the inhibition of the entry processes, an accurate functional relationship between the CD4/CCR5 concentrations and infectivity is desired in order to more quantitatively analyze experimental data. We propose three kinetic models describing the possible mechanistic processes involved in HIV entry and fit their predictions to infectivity measurements, contrasting and comparing different outcomes. Our approach allows interpretation of the clustering of infectivity of different strains of HIV-1 in the space of mechanistic kinetic parameters. Our model fitting also allows inference of nontrivial stoichiometries of receptor and coreceptor binding and provides a framework through which to quantitatively investigate the effectiveness of fusion inhibitors and neutralizing antibodies.
authors.affiliation: Department of Biomathematics, University of California , Los Angeles, California 90095, United States.
authors.forename: Bhaven
authors.initials: B
authors.lastname: Mistry
authors.affiliation: Department of Biomathematics, University of California , Los Angeles, California 90095, United States.|Department of Mathematics, California State University , Northridge, California 91330, United States.
authors.forename: Maria R
authors.initials: MR
authors.lastname: D'Orsogna
authors.affiliation: Department of Infectious Disease, Children's Hospital Los Angeles , Los Angeles, California 90027, United States.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Webb
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Biomathematics, University of California , Los Angeles, California 90095, United States.|Department of Mathematics, University of California , Los Angeles, California 90095, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Chou
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D019713:Receptors, CCR5 / Q000378:metabolism*; D014774:Virulence; D053586:Virus Internalization / Q000187:drug effects; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus