Correlation between neurological progression and astrocyte apoptosis in HIV‐associated dementia

The pathogenesis of HIV‐associated dementia (HIVD) has been postulated to be due to the indirect effects of HIV infection, including the aberrant central nervous system production of cytokines and other neurotoxins. A correlation between the severity of dementia and production of neurotoxins in HIVD has been demonstrated. We have previously identified nonproductive HIV infection of astrocytes. Because astrocytes participate in the inactivation of neurotoxins, we hypothesize that HIV nonproductive infection of astrocytes may lead to an environment in which there is a significant level of astrocyte apoptosis and a consequent increase in the levels of neurotoxins and that this results in more rapidly progressing dementia. Postmortem brain tissue was examined from clinically well‐characterized HIV‐positive demented patients, HIV‐positive nondemented patients, and HIV‐seronegative nondemented control subjects. The HIVD group was further categorized into subjects with rapid and those with slow progression of dementia. Tissue was paraformaldehyde fixed and paraffin embedded, and 6‐μm sections from the basal ganglia and mid‐frontal gyrus were processed to detect apoptosis by in situ transferase dUTP nick end labeling. Astrocytes were co‐localized using immunohistochemical techniques. In situ polymerase chain reaction (PCR) techniques were utilized to detect HIV DNA in astrocytes. The density of apoptotic astrocytes was significantly greater in the HIV‐positive groups than in the HIV‐negative group (p < 0.01). The HIVD rapid progressors had a significantly greater number of apoptotic astrocytes in the basal ganglia than did the HIVD slow progressors (p < 0.05). In addition, there were a greater number of HIV DNA–positive astrocytes, as demonstrated by in situ PCR, in the HIVD rapid progressors than in the slow progressor and HIV‐nondemented groups. These data suggest that there is an increased rate of astrocyte loss in the subjects with rapidly progressive dementia, in association with an increased number of HIV DNA–positive astrocytes. The results emphasize the importance of understanding more completely the role of HIV infection of astrocytes in the neuropathogenesis of HIVD.

[1]  S. Love,et al.  Apoptosis and expression of DNA repair proteins in ischaemic brain injury in man , 1998, Neuroreport.

[2]  S. Wesselingh,et al.  Detection of cytokine mRNA in astrocyte cultures using the polymerase chain reaction. , 1990, Lymphokine research.

[3]  E. Major,et al.  Persistent human immunodeficiency virus type 1 infection in human fetal glial cells reactivated by T-cell factor(s) or by the cytokines tumor necrosis factor alpha and interleukin-1 beta , 1991, Journal of virology.

[4]  J. Becker,et al.  Dementia in AIDS patients , 1993, Neurology.

[5]  F. Scaravilli,et al.  Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. , 1999, Journal of neuropathology and experimental neurology.

[6]  J. Glass,et al.  Immunocytochemical quantitation of human immunodeficiency virus in the brain: Correlations with dementia , 1995, Annals of neurology.

[7]  S. Lipton.  Models of neuronal injury in AIDS: another role for the NMDA receptor? , 1992, Trends in Neurosciences.

[8]  H. Gendelman,et al.  Human immunodeficiency virus type 1 infection of the nervous system: Pathogenetic mechanisms , 1993, Annals of neurology.

[9]  E. Major,et al.  HIV‐1 infection of subcortical astrocytes in the pediatric central nervous system , 1994, Neurology.

[10]  D. Griffin,et al.  Perspectives Series : Cytokines and the Brain Cytokines in the Brain during Viral Infection : Clues to HIV-associated Dementia , 1997 .

[11]  C. Decastro,et al.  Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Chrétien,et al.  Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage , 1999, Neuropathology and applied neurobiology.

[13]  L. Prockop.  AIDS dementia complex. , 1988, The Journal of legal medicine.

[14]  F. Scaravilli,et al.  HIV‐1 DNA in brains in AIDS and pre‐AIDS: Correlation with the stage of disease , 1996, Annals of neurology.

[15]  H. Gendelman,et al.  Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease , 1992, The Journal of experimental medicine.

[16]  J. Glass,et al.  Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase/polymerase chain reaction in situ hybridization and immunohistochemistry , 1997, Journal of Neuroimmunology.

[17]  J. Kort.  Impairment of excitatory amino acid transport in astroglial cells infected with the human immunodeficiency virus type 1. , 1998, AIDS research and human retroviruses.

[18]  R. Brack-Werner.  Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. , 1999, AIDS.

[19]  P. Walker,et al.  CD95 (Fas/Apo-1) as a receptor governing astrocyte apoptotic or inflammatory responses: a key role in brain inflammation? , 1999, Journal of immunology.

[20]  C. Cotman,et al.  DNA Damage and Activated Caspase-3 Expression in Neurons and Astrocytes: Evidence for Apoptosis in Frontotemporal Dementia , 2000, Experimental Neurology.

[21]  P. Lieberman,et al.  Cloning of a transcriptionally active human TATA binding factor. , 1990, Science.

[22]  J. Glass,et al.  Cytokine expression in the brain during the acquired immunodeficiency syndrome , 1992, Annals of neurology.

[23]  J. Glass,et al.  Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dememtia , 1993, Annals of neurology.

[24]  M. Louder,et al.  Overexpression of nef as a marker for restricted HIV‐1 infection of astrocytes in postmortem pediatric central nervous tissues , 1994, Neurology.

[25]  O. Selnes,et al.  Clinical‐neuropathologic correlation in HIV‐associated dementia , 1993, Neurology.

[26]  O. Selnes,et al.  Variable progression of HIV‐associated dementia , 1998, Neurology.

[27]  J. Glass,et al.  Cytokine dysregulation in HIV-associated neurological disease. , 1994, Advances in neuroimmunology.

[28]  S. Wesselingh,et al.  Elevated central nervous system prostaglandins in human immunodeficiency virus—associated dementia , 1994, Annals of neurology.

[29]  D. Attwell,et al.  The release and uptake of excitatory amino acids. , 1990, Trends in pharmacological sciences.

[30]  U. de Girolami,et al.  Apoptosis induced by HIV-1 infection of the central nervous system. , 1996, The Journal of clinical investigation.

[31]  J. Li,et al.  Cell surface morphology identifies microglia as a distinct class of mononuclear phagocyte , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  C. Petito,et al.  Effect of Postmortem Interval on In Situ End-Labeling of DNA Oligonucleosomes , 1995, Journal of neuropathology and experimental neurology.

[33]  T. Crawford,et al.  Cerebral white matter changes in acquired immunodeficiency syndrome dementia: Alterations of the blood‐brain barrier , 1993, Annals of neurology.

[34]  W. Hickey.  Migration of Hematogenous Cells Through the Blood‐Brain Barrier and the Initiation of CNS Inflammation , 1991, Brain pathology.

[35]  M. Shin,et al.  Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. , 1987, Journal of immunology.

[36]  C. Power,et al.  HIV-1 Associated Dementia: Clinical Features and Pathogenesis , 1995, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[37]  J. Glass,et al.  Localization of HIV‐1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry , 1996, Annals of neurology.

[38]  J. Rothstein,et al.  Tumor Necrosis Factor (cid:97) Inhibits Glutamate Uptake by Primary Human Astrocytes FOR PATHOGENESIS OF HIV-1 , 2022 .

[39]  S. Snyder,et al.  Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[40]  G. Pavlakis,et al.  Restriction of human immunodeficiency virus type 1 production in a human astrocytoma cell line is associated with a cellular block in Rev function , 1995, Journal of virology.

[41]  R. Mrak,et al.  Glial Cytokines as Neuropathogenic Factors in HIV Infection: Pathogenic Similarities to Alzheimer's Disease , 1994, Journal of neuropathology and experimental neurology.

[42]  S. Lipton.  Neuronal injury associated with HIV-1: approaches to treatment. , 1998, Annual review of pharmacology and toxicology.