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Chapter 20 : Persistent Infections
Category: Viruses and Viral Pathogenesis
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Once considered rare, persistent virus infections in animals and humans are no longer thought uncommon. Such persistent infections may culminate in pathological changes or, after a prolonged incubation period, overt disease. Persistent virus infections in livestock, such as foot-and-mouth disease virus (FMDV) infection, also can have substantial economic consequences. Well-characterized models are needed to improve the understanding of the mechanisms underlying persistent viral infections. Several members of the Picornaviridae family produce persistent infections in their natural hosts, with FMDV infection in cloven-hoofed cattle and Theiler's murine encephalomyelitis virus (TMEV) infection in mice as the best-characterized examples. CD155-negative mouse LM cells transfected with mutated CD155 cDNA from cured IMR-32 cells also showed partial resistance to poliovirus (PV)-induced cytolysis and apoptosis compared to cells transfected with nonmutated CD155 cDNA. Noncytolytic FMDV mutants were isolated after repeated transfers and established persistent infections in BHK-21 cells without cell crisis. Enteroviruses, primarily coxsackievirus B (CVB), have been associated with the development of dilated cardiomyopathies, for which about 30% of patients have a history of acute mycocarditis. Once considered rare, persistent virus infections in animals and humans are no longer uncommon. Persistent picornavirus infections in cells in culture have provided important models for elucidating the mechanisms underlying virus persistence.
Schematic representation of persistent and latent infection patterns exemplified by HIV, human HCV, human HBV, human papillomavirus (HPV), herpes simplex virus (HSV), CVB, and PV infections. HCC, hepatocellular carcinoma.
Simplified models of persistent PV infection in human cells. (A) Neuronal cell model. During establishment of a persistent PV infection, cellular factors are of crucial importance. Some infected neuronal cells are lysed, whereas other survive infection. Days to weeks after infection, cells express CD155 forms mutated in the PV-binding domain, and PV mutants (PVpi) are continuously produced in the absence of obvious cytopathic effects. PVpi are more lytic than reference PV strains in neuronal cells but less lytic than these strains in epithelial cells. (B) Epithelial cell model. During establishment of a persistent PV infection in human cells of epidermoid or intestinal origin, the virus (PVpi) and the multiplicity of infection (MOI) are of central importance. Virus and cells coevolve, with maintenance of the persistent infection relying on an equilibrium between abortive and PV cytolytic infection. Dark and light gray octagons, PVpi and other PV mutants, respectively; pi cell, persistently PV-infected cell; thin and thick arrows, virus and cell evolution, respectively.
Induction of pro- and antiapoptotic signaling pathways in human neuroblastoma cells following PV infection. Activation of the apoptotic mitochondrial pathway in PV-infected neuronal IMR-5 cells is Bax dependent and mediated by early JNK activation. Activation of the PI3K/Akt survival pathway limits PV-induced JNK-mediated cell death through negative regulation of ASK1 acting upstream of JNK. (Adapted from reference 8 , DOI no. 10. 2741/3370.)
TMEV persistence in the mouse CNS. (A) Model of TMEV persistence where there is continuous macrophage-to-macrophage viral spread. Macrophages undergo apoptosis and restrict TMEV yields, whereas oligodendrocytes are productively infected and undergo necrosis. Growth kinetics in macrophages has revealed exponential virus RNA replication and normal protein translation and virion assembly but restricted final infectious virus yields. Limited amounts of infectious virus and apoptotic blebs or remnants containing virus are shown infecting another macrophage (top) and an oligodendrocyte (lower center). Virus antigen(s) in cells and apoptotic remnants are denoted by stippling. (B) Proposed pathway for permeabilization of the mitochondrial outer membrane to induce apoptosis during TMEV infection in murine macrophages.