A 46-year-old woman with relapsing–remitting multiple sclerosis died from progressive multifocal leukoencephalopathy (PML) after having received 37 doses of natalizumab (300 mg every four weeks) as part of a clinical trial of natalizumab and interferon beta-1a. PML was diagnosed on the basis of the finding of JC viral DNA in cerebrospinal fluid on polymerase-chain-reaction assay and was confirmed at autopsy. Nearly every tissue section from bilateral cerebral hemispheres contained either macroscopic or microscopic PML lesions. There was extensive tissue destruction and cavitation in the left frontoparietal area, large numbers of bizarre astrocytes, and inclusion-bearing oligodendrocytes, which were positive for JC virus DNA on in situ hybridization.

Herpes simplex virus infection of mammalian hosts involves lytic replication at a primary site, such as the cornea, translocation by axonal transport to sensory ganglia and replication, and latent infection at a secondary site, ganglionic neurons. The virus-encoded thymidine kinase, which is a target for antiviral drugs such as acyclovir, is not essential for lytic replication yet evidently is required at the secondary site for replication and some phase of latent infection. To determine the specific stage in viral pathogenesis at which this enzyme is required, we constructed virus deletion mutants that were acyclovir resistant and exhibited no detectable thymidine kinase activity. After corneal inoculation of mice, the mutants replicated to high titers in the eye but were severely impaired for acute replication in trigeminal ganglia and failed to reactivate from ganglia upon cocultivation with permissive cells. Nevertheless, latency-associated transcripts were expressed in neuronal nuclei of ganglia from mutant-infected mice and superinfection of the ganglia with a second virus rescued the latent mutant virus. Thus, contrary to a widely accepted hypothesis, the thymidine kinase-negative mutants established latent infections, implying that neither thymidine kinase activity nor ganglionic replication is necessary for establishment of latency. Rather, thymidine kinase appears to be necessary for reactivation from latency. These results suggest that acyclovir-resistant viruses could establish latent infections in clinical settings and have implications for the use of genetically engineered herpesviruses to deliver foreign genes to neurons.

Encephalitis is characterized by fever, neurologic deficits, seizures, pleocytosis, and neuroimaging and EEG abnormalities. The main viral causes segregate into characteristic clinical, imaging, and regional profiles. Early acyclovir treatment of herpes encephalitis is beneficial.

MEK kinase 1 (MEKK1) is a 196-kDa mitogen-activated protein kinase (MAPK) kinase kinase that, in addition to regulating the c-Jun NH ₂ -terminal kinase (JNK) pathway, is involved in the control of cell motility. MEKK1 ^−/− mice are defective in eyelid closure, a TGFα-directed process involving the migration of epithelial cells. MEKK1 expression in epithelial cells stimulates lamellipodia formation, a process required for cell movement. In addition, mouse embryo fibroblasts derived from MEKK1 ^−/− mice are inhibited in their migration relative to MEKK1 ^+/+ fibroblasts. MEKK1 is required for JNK but not NF-κB activation in response to virus infection, microtubule disruption, and stimulation of embryonic stem cells with lysophosphatidic acid. MEKK1 is not required for TNFα or IL-1 regulation of JNK or NF-κB activation in macrophages or fibroblasts. Thus, MEKK1 senses microtubule integrity, contributes to the regulation of fibroblast and epithelial cell migration, and is required for activation of JNK but not NF-κB in response to selected stress stimuli.