title: A Computational Model of Inhibition of HIV-1 by Interferon-Alpha.
abstract: Type 1 interferons such as interferon-alpha (IFNα) inhibit replication of Human immunodeficiency virus (HIV-1) by upregulating the expression of genes that interfere with specific steps in the viral life cycle. This pathway thus represents a potential target for immune-based therapies that can alter the dynamics of host-virus interactions to benefit the host. To obtain a deeper mechanistic understanding of how IFNα impacts spreading HIV-1 infection, we modeled the interaction of HIV-1 with CD4 T cells and IFNα as a dynamical system. This model was then tested using experimental data from a cell culture model of spreading HIV-1 infection. We found that a model in which IFNα induces reversible cellular states that block both early and late stages of HIV-1 infection, combined with a saturating rate of conversion to these states, was able to successfully fit the experimental dataset. Sensitivity analysis showed that the potency of inhibition by IFNα was particularly dependent on specific network parameters and rate constants. This model will be useful for designing new therapies targeting the IFNα network in HIV-1-infected individuals, as well as potentially serving as a template for understanding the interaction of IFNα with other viruses.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Browne
authors.affiliation: Operations Research Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Letham
authors.affiliation: Operations Research Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Sloan School of Management, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rudin
mesh_terms: D000465:Algorithms; D000998:Antiviral Agents / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D003198:Computer Simulation; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007113:Immunity, Innate; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000737:chemistry*; D015233:Models, Statistical; D015203:Reproducibility of Results; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha