RESUMEN
MOTIVATION: Human immunodeficiency virus type 1 (HIV-1) hijacks host cellular processes to replicate within its host. Through interactions with host proteins, it perturbs and interrupts signaling pathways that alter key cellular functions. Although networks of viral-host interactions have been relatively well characterized, the dynamics of the perturbation process is poorly understood. Dynamic models of infection have the potential to provide insights into the HIV-1 host interaction. RESULTS: We employed a logical signal flow network to model the dynamic interactions between HIV-1 proteins and key human signal transduction pathways necessary for activation of CD4+ T lymphocytes. We integrated viral-host interaction and host signal transduction data into a dynamic logical model comprised of 137 nodes (16 HIV-1 and 121 human proteins) and 336 interactions collected from the HIV-1 Human Interaction Database. The model reproduced expected patterns of T-cell activation, co-stimulation and co-inhibition. After simulations, we identified 26 host cell factors, including MAPK1&3, Ikkb-Ikky-Ikka and PKA, which contribute to the net activation or inhibition of viral proteins. Through in silico knockouts, the model identified a further nine host cell factors, including members of the PI3K signalling pathway that are essential to viral replication. Simulation results intersected with the findings of three siRNA gene knockout studies and identified potential drug targets. Our results demonstrate how viral infection causes the cell to lose control of its signalling system. Logical Boolean modelling therefore provides a useful approach for analysing the dynamics of host-viral interactions with potential applications for drug discovery. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Asunto(s)
Infecciones por VIH/inmunología , VIH-1/metabolismo , Modelos Logísticos , Activación de Linfocitos/inmunología , Transducción de Señal , Linfocitos T/inmunología , Proteínas Virales/metabolismo , Biología Computacional/métodos , Bases de Datos de Proteínas , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Mapeo de Interacción de Proteínas , Proteínas Virales/inmunología , Replicación ViralRESUMEN
Accumulation of modified nucleotides is defective to various cellular processes, especially those involving DNA and RNA. To be viable, organisms possess a number of (deoxy)nucleotide phosphohydrolases, which hydrolyze these nucleotides removing them from the active NTP and dNTP pools. Deamination of purine bases can result in accumulation of such nucleotides as ITP, dITP, XTP and dXTP. E. coli RdgB has been characterised as a deoxyribonucleoside triphosphate pyrophosphohydrolase that can act on these nucleotides. S. cerevisiae homologue encoded by YJR069C was purified and its (d)NTPase activity was assayed using fifteen nucleotide substrates. ITP, dITP, and XTP were identified as major substrates and kinetic parameters measured. Inhibition by ATP, dATP and GTP were established. On the basis of experimental and published data, modelling and simulation of ITP, dITP, XTP and dXTP metabolism was performed. (d)ITP/(d)XTPase is a new example of enzyme with multiple substrate-specificity demonstrating that multispecificity is not a rare phenomenon.