A rat model of human immunodeficiency virus 1 encephalopathy using envelope glycoprotein gp120 expression delivered by SV40 vectors.
Human immunodeficiency virus 1 (HIV-1) encephalopathy is thought to result in part from the toxicity of HIV-1 envelope glycoprotein gp120 for neurons. Experimental systems for studying the effects of gp120 and other HIV proteins on the brain have been limited to the acute effects of recombinant proteins in vitro or in vivo in simian immunodeficiency virus-infected monkeys. We describe an experimental rodent model of ongoing gp120-induced neurotoxicity in which HIV-1 envelope is expressed in the brain using an SV40-derived gene delivery vector, SV(gp120). When it is inoculated stereotaxically into the rat caudate putamen, SV(gp120) caused a partly hemorrhagic lesion in which neuron and other cell apoptosis continues for at least 12 weeks. Human immunodeficiency virus gp120 is expressed throughout this time, and some apoptotic cells are gp120 positive. Malondialdehyde and 4-hydroxynonenal assays indicated that there was lipid peroxidation in these lesions. Prior administration of recombinant SV40 vectors carrying antioxidant enzymes, copper/ zinc superoxide dismutase or glutathione peroxidase, was protective against SV(gp120)-induced oxidative injury and apoptosis. Thus, in vivo inoculation of SV(gp120) into the rat caudate putamen causes ongoing oxidative stress and apoptosis in neurons and may therefore represent a useful animal model for studying the pathogenesis and treatment of HIV-1 envelope-related brain damage.
Louboutin
Jean-Pierre
JP
Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA. jplouboutin@hotmail.com
Agrawal
Lokesh
L
Reyes
Beverly A S
BA
Van Bockstaele
Elisabeth J
EJ
Strayer
David S
DS
D015526:AIDS Dementia Complex / Q000209:etiology* / Q000235:genetics; D000261:Adenoviruses, Simian; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D005822:Genetic Vectors / Q000008:administration & dosage; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000009:adverse effects* / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles; D008840:Microfilament Proteins; D009474:Neurons / Q000473:pathology / Q000821:virology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011699:Putamen / Q000821:virology; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods
C112986:AIF1 protein, human; D000447:Aldehydes; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D015699:HIV Envelope Protein gp120; D007211:Indoles; D008840:Microfilament Proteins; C007293:DAPI; D005979:Glutathione Peroxidase; D010751:Phosphopyruvate Hydratase; C027576:4-hydroxy-2-nonenal