Human Immunodeficiency virus type 1 protein gp120 causes neuronal cell death in the rat brain by activating caspases

Abstract

Human immunodeficiency virus type 1 (HIV-1)infection of the central nervous system is associated with microglia activation and neuronal apoptosis, alterations that are also caused by the HIV-1 envelope glycoprotein 120 (gp120) alone. This study was undertaken to examine the onset of gp120 neurotoxicity, the type of cell death and which cells of the adult rat brain are more sensitive to the toxic action of gp120. Gp120 or vehicle were injected chronically (daily for 3 or 7 days) into the lateral ventricle. Magnetic resonance imaging revealed hypertensive areas in the cortical and hippocampal gray matter in gp120-treated rats 7-10 days after the first injection, suggesting vasogenic edema. This phenomenon was accompanied by an enlargement of the lateral and third ventricles. Immunohistochemical analyses were then carried out to examine the toxic effect of gp120 at a cellular level. Several markers of apoptosis, including activated caspase-3 were observed at both 3 and 7 days throughout brains of gp120-treated rats, especially in the cerebral cortex. In this area, most of the apoptotic cells exhibited a pyramidal shape and were Nissl positive, indicative of neurons. Few non-neuronal cells exhibited signs of apoptosis. The results of the present study support the notion that gp120 is neurotoxic in vivo and provide evidence that gp120 activates a caspasedependent apoptotic pathway.

Axonal Transport of Human Immunodeficiency Virus Type 1 Envelope Protein Glycoprotein 120 Is Found in Association with Neuronal Apoptosis

“…After three washes, sections were incubated with Alexa-Fluor 488 and Alexa-Fluor 594 secondary antibodies to visualize gp120 and caspase-3, respectively. For in situ terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) and gp120, sections were incubated with gp120 antibody overnight at 4°C, and then TUNEL was performed as described previously (Bachis et al, 2003;Acquas et al, 2004). All sections were then mounted using Vectashield mounting medium (Vector Laboratories, Burlingame, CA).…”

“…Moreover, SDF, which is present at high levels in the brain of HIVinfected individuals, induces neuronal apoptosis in rodent brain (Zhang et al, 2003) as well as in vitro (Hesselgesser et al, 1998;Zheng et al, 1999;Bachis and Mocchetti, 2004). Similarly, overexpression of gp120 in transgenic mice (Toggas et al, 1994) or intracerebroventricular infusion of this glycoprotein in rat brain (Bagetta et al, 1996;Bansal et al, 2000;Maccarrone et al, 2000;Acquas et al, 2004) promotes degeneration of neurons, loss of dendritic markers, ventricular enlargement, and other severe neuronal abnormalities that are commonly seen in ADC patients.…”

Characterization of Cell Death Pathways in Human Immunodeficiency Virus-Associated Encephalitis

“…1,[12][13][14] In transgenic animals, gp120 (which is one of the proteins derived from the env gene of HIV-1) is neurotoxic and activates caspase-dependent apoptosis. 15 Accordingly, active caspase-3 16 and p53 17 have been detected in the brain of HAE patients.…”

Intrastriatal administration of human immunodeficiency virus‐1 glycoprotein 120 reduces glial cell‐line derived neurotrophic factor levels and causes apoptosis in the substantia nigra

“…Because the correlation between viral load and the severity of neurodegeneration in ADC is often weak, experimental models of ADC have explored the contribution of indirect neurotoxic mechanisms. Models in which viral proteins are injected into rodent brain have shown activation of caspase-3 and other apoptotic markers in neurons followed by neuronal loss (Bagetta et al, 1995Corasaniti et al, 1998;Kruman et al, 1998;Zheng et al, 1999;Kaul et al, 2001;Acquas et al, 2004). However, there is still debate as to whether the effect of gp120 or other viral proteins can account for the extensive neuronal loss observed in HIV-positive patients.…”

“…Sections were then incubated with fluorophore-conjugated secondary antibodies (Alexafluor; 1:1500 dilution; Molecular Probes, Carlsbad, CA) for 30 min at RT and mounted with mounting medium containing 4 0 ,6 0 -diamidino-2-phenylindole (DAPI) as nuclear counterstaining (Vector Laboratories, Burlingame, CA). Serial sections were also labeled for in situ terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) as previously described (Bachis et al, 2003;Acquas et al, 2004) using ApopTag (Serological Corporation, Norcross, GA).…”