Neuropathology of NFHgp160 Transgenic Mice Expressing HIV-1 Env protein in Neurons

Abstract

The physiopathology of HIV-1 dementia remains largely hypothetical. Although several sets of evidence point towards an indirect multicellular inflammatory pathway, gp120, one of the HIV-1 env products, was shown to be very cytotoxic for neurons in vitro. To explore a direct pathway in the physiopathology of dementia in AIDS, we developed transgenic mouse models carrying the HIV-1 env proteins gp 120 and gp 41 (gp 160) under the control of the human light neurofilament and murine heavy neurofilament promoters. To date, this is the first mouse model in which the HIV-1 env protein can be detected in neurons by immunohistochemistry. The expression is found in several brainstem and spinal cord gray structures and in the cerebellum in one of the mouse lines bearing the NFHgp160 transgene. The morphological findings at 3 months are subtle and are dominated by a watery, dendritic degeneration and a reactive gliosis. At 12 months, the evidence of neuronal degeneration and loss is present along with various degenerative phenomena involving synapses, dendrites and axons, including axonal swellings. Cytoskeletal abnormalities were found by immunohistochemistry. Chronic inflammation was also observed in the leptomeninges of the spinal cord and brainstem and in the cerebellar white matter. These models thus offer an exciting sequence of morphological findings initiated by the neuronal expression of the HIV-1 env proteins and offer a different tool to explore the neuronal dysfunction in AIDS.

Ethanol-related increases in degenerating bodies in the Purkinje neuron dendrites of aging rats

“…Myelin figures, however, have been observed in unfixed specimens (Cole and Adldrich, 1971), well fixed tissue (Morara et al, 1990), human diseases (Tani et al, 1971;Park et al, 1999), and a wide range of species including humans (Tani et al, 1971), fungi (Cole and Aldrich, 1971), and zebrafish (Anken et al, 2004). In the present study as in many of the other studies cited above in which myelin figures were detected (Feldman, 1976;Haglid et al, 1981;Casey and Feldman, 1985;Malunova and Samolilov, 1984;Iontov and Shefer, 1991;Morara et al 1990 ;Wakayama et al, 1992;Kriebel et al, 1993;Peters et al, 1994;Chen and Hillman, 1999;Michaud et al, 2001), the normal appearance of the tissue argues against myelin figures representing fixation artifact. Furthermore, it is unlikely that the present finding of ethanol-related increases in degenerating structures within PN dendrites would have resulted from a fixation artifact.…”

“…In the rats treated with ethanol for 20 to 40 weeks, the SER profiles appeared swollen or dilated, a finding that has been confirmed quantitatively (Dlugos and Pentney 2002;Dlugos 2006 a;Dlugos, 2006 b). In some of the PN dendritic shafts and branchlets, degenerating bodies were observed similar to that which has been shown in a host of various diseases and experimental conditions (Feldman, 1976;Iontov and Shefer, 1981;Malunova andSamoilov, 1984: Kriebel et al, 1993;Peters et al, 1994;Michaud et al, 2001;Morora et al, 2001;Dlugos 2006 a, b). Degenerating bodies appeared as whorls of membrane, termed myelin figures (Morora et al, 2001) (Fig 2 C,D, E) or as membrane bound structures with a center core of smaller membrane-bound vesicles (Fig 2 A, B, F).…”

“…Degenerating bodies are not unique to PN dendrites as they are present in dendrites of the cerebral cortex (Feldman, 1976;Iontov and Shefer, 1991;Peters et al, 1994) and brainstem (Casey and Feldman, 1985). Similarly, degenerating body formation is not a unique effect of chronic ethanol consumption as degenerating bodies are present in hydrocephalus (Kriebel et al, 1993) aluminum intoxication (Wakayama et al, 1992), and HIV (human deficiency virus) (Michaud et al, 2001), over-expression of tau (Hall et al, 2000), anoxia (Malunova and Samolilov, 1984), and trichloroethylene treatment (Haglid et al, 1981).…”

“…Degenerating bodes are not unique to PN dendrites as similar structures have been repeatedly observed in other neurons and neuronal processes and have been given a variety of labels including dense bodies (Babel et al, 1970), myelin ovoids (Pavelka and Roth, 2005), vacuoles (Feldman;1976), membranous inclusions (Feldman, 1976), myelin figures (Morara et al, 2001), and membranes in the stages of destruction (Bogleopov, 1981). Degenerating bodies occur in cortical neurons (Feldman, 1976;Iontov and Shefer, 1991;Peters et al, 1994), PN (Chen and Hillman, 1999), and brainstem neurons (Casey and Feldman, 1985) and are present in pathologies such as hydrocephalus (Kriebel et al, 1993), chronic tau expression (Hall et al, 2000), HIV (human immunodeficiency virus) (Michaud et al, 2001), anoxia (Malunova and Samolilov, 1984), and aluminum intoxication (Wakayama et al, 1992).…”

A Critical Determinant of Neurological Disease Associated with Highly Pathogenic Tick-Borne Flavivirus in Mice

“…Rabies infection induces electrophysiological alterations, including effects on ion channels and neurotransmission, which may be the cause of functional impairment (38). Alterations in synaptic function have been also reported in borna disease virus and human immunodeficiency virus (HIV) infections (39,40), whereas axonal degeneration is instrumental in the development of neuronal dysfunction during herpesvirus and HIV infections (41)(42)(43)(44). Despite these clear associations between neurotropic viruses and neuronal dysfunction, the majority of research examining neurological diseases caused by tick-borne flaviviruses has focused on virus-induced cytopathic effects or immunopathogenic responses.…”