Role of animal models in the study of drug-induced hypersensitivity reactions

Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very difficult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basis hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ∼0.25%, and large-breed dogs are difficult to use as an animal model. Two more practical models are penicillamine-induced auto-immunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquine-induced agranulocytosis/hepatotoxicity and halothane-induced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This finding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also significantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow

Probing the biophysical interplay between a viral genome and its capsid

The interaction between a viral capsid and its genome governs crucial steps in the life cycle of a virus, such as assembly and genome uncoating. Tuning cargo–capsid interactions is also essential for successful design and cargo delivery in engineered viral systems. Here we investigate the interplay between cargo and capsid for the picorna-like Triatoma virus using a combined native mass spectrometry and atomic force microscopy approach. We propose a topology and assembly model in which heterotrimeric pentons that consist of five copies of structural proteins VP1, VP2 and VP3 are the free principal units of assembly. The interpenton contacts are established primarily by VP2. The dual role of the genome is first to stabilize the densely packed virion and, on an increase in pH, second to trigger uncoating by relaxing the stabilizing interactions with the capsid. Uncoating occurs through a labile intermediate state of the virion that reversibly disassembles into pentons with the concomitant release of protein VP4.Fil: Snijder, J.. Netherlands Proteomics Centre; Países Bajos. Utrecht Univeristy; Países Bajos. Vrije Universiteit; Países BajosFil: Uetrecht, C.. Netherlands Proteomics Centre; Países Bajos. Utrecht Univeristy; Países BajosFil: Rose, R. J.. Netherlands Proteomics Centre; Países Bajos. Utrecht Univeristy; Países BajosFil: Sanchez Eugenia, R.. Universidad del Pais Vasco; EspañaFil: Marti, Gerardo Anibal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Estudios Parasitológicos y de Vectores (i); Argentina. Universidad Nacional de La Plata; ArgentinaFil: Agirre, J.. Universidad del Pais Vasco; España. Fundación Biofisica Bizkaia; EspañaFil: Guérin, D. M. A.. Universidad del Pais Vasco; España. Fundación Biofisica Bizkaia; EspañaFil: Wuite, G. J. L.. Vrije Universiteit; Países BajosFil: Heck, A. Netherlands Proteomics Centre; Países Bajos. Utrecht Univeristy; Países BajosFil: Roos, W. H.. Vrije Universiteit; Países Bajo