In general, virus infections of the brain are rather rare in the immune competent host. However, neurotropic viruses have developed mechanisms to exploit weaknesses in immunological defense mechanisms that eventually allow them to reach and infect CNS neurons. Once in the CNS, these viruses can induce significant neuronal dysfunction and degeneration of specific neuronal populations, sometimes leading to devastating, life-threatening consequences for the host. Here, we examine viruses with the ability to infect neurons and their resulting pathologies, their modes of entry to the CNS, and the cellular and molecular alterations that these viruses induce in neuronal cells. We also discuss the importance of various pathogenic events associated with viral infection of neurons and elaborate on the implications of recent findings suggesting that neuronal cells affected by viruses undergo a "dying back" pattern of degeneration. Finally, findings of virus-induced alterations in kinase activity are discussed in the context of recent evidence linking abnormalities in kinase signaling to the pathogenesis of major human neurodegenerative conditions.

The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity.

The microstructure changes associated with degeneration of spinal axons in amyotrophic lateral sclerosis (ALS) may be reflected in altered water diffusion properties, potentially detectable with diffusion-weighted (DW) MRI. Prior work revealed the classical mono-exponential model fails to precisely depict decay in DW signal at high b-values. In this study, we aim to investigate signal decay behaviors at ultra-high b-values for non-invasive assessment of spinal cord alterations in the transgenic SOD1 G93A mouse model of ALS. A multiexponential diffusion analysis using regularized non-negative least squares (rNNLS) algorithm was applied to a series of thirty DW MR images with b-values ranging from 0 to 858,022 s/ mm 2 on ex vivo spinal cords of transgenic SOD1 G93A and age-matched control mice. We compared the distributions of measured diffusion coefficient fractions between the groups. The measured diffusion weighted signals in log-scale showed non-linear decay behaviors with increased b-values. Faster signal decays were observed with diffusion gradients applied parallel to the long axis of the spinal cord compared to when oriented in the transverse direction. Multiexponential analysis at the lumbar level in the spinal cord identified ten subintervals. A significant decrease of diffusion coefficient fractions was found in the ranges of [1.63×10 −8 ,3.70×10 −6 ] mm 2 /s (P = 0.0002) and of [6.01×10 −6 ,4.20×10 −5 ] mm 2 /s (P = 0.0388) in SOD1 G93A mice. Anisotropic diffusion signals persisted at ultra-high b-value DWIs of the mouse spinal cord and multiexponential diffusion analysis offers the potential to evaluate microstructural alterations of ALS-affected spinal cord non-invasively.

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