M- and T-tropic HIVs Promote Apoptosis in Rat Neurons

被引:37
作者
Bachis, Alessia [1 ]
Biggio, Francesca [1 ]
Major, Eugene O. [2 ]
Mocchetti, Italo [1 ]
机构
[1] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA
[2] NINDS, Lab Mol Med & Neurosci, Bethesda, MD 20814 USA
关键词
acquired immune deficiency syndrome-associated dementia complex; gp120; neuronal apoptosis; CXCR4; CCR5; AMD3100; DAPTA; HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; CHEMOKINE RECEPTOR CXCR4; LASER CAPTURE MICRODISSECTION; CEREBELLAR GRANULE CELLS; AIDS DEMENTIA COMPLEX; NECROSIS-FACTOR-ALPHA; NEUROTROPHIC FACTOR; HUMAN BRAIN; NMDA RECEPTOR;
D O I
10.1007/s11481-008-9141-3
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Neuronal loss, reactive astrocytes, and other abnormalities are seen in the brain of individuals with acquired immune deficiency syndrome-associated Dementia Complex (ADC). Human immunodeficiency virus-1 (HIV-1) is believed to be the main agent causing ADC. However, little is known about the molecular and cellular mechanisms of HIV-1 neurotoxicity considering that HIV-1 does not infect post-mitotic neurons and that viral load does not necessarily correlate with ADC. Various viral proteins, such as the envelope protein gp120 and the transcription activator Tat, have been shown to induce neuronal apoptosis through direct and indirect mechanisms both in vitro and in vivo. Progeny HIV-1 virions can also cause neuronal death. However, it has not been fully established yet whether HIV-1 promotes neuronal apoptosis by a direct mechanism. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-1, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCR5 coreceptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in cell lysates. Instead, neurons were gp120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCR5 receptor inhibitor d-Ala-peptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the N-methyl-d-aspartate receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp120 binding to neuronal chemokine receptors.
引用
收藏
页码:150 / 160
页数:11
相关论文
共 71 条
[1]   Migration and differentiation of neural precursor cells can be directed by microglia [J].
Aarum, J ;
Sandberg, K ;
Haeberlein, SLB ;
Persson, MAA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (26) :15983-15988
[2]   NEURONAL APOPTOSIS IN HIV-INFECTION IN ADULTS [J].
ADLEBIASSETTE, H ;
LEVY, Y ;
COLOMBEL, M ;
PORON, F ;
NATCHEV, S ;
KEOHANE, C ;
GRAY, F .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 1995, 21 (03) :218-227
[3]   The chemokine receptor CXCR4 and not the N-methyl-D-aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells [J].
Bachis, A ;
Mocchetti, I .
JOURNAL OF NEUROSCIENCE RESEARCH, 2004, 75 (01) :75-82
[4]  
Bachis A, 2003, J NEUROSCI, V23, P5715
[5]   Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity [J].
Bachis, A ;
Colangelo, AM ;
Vicini, S ;
Doe, PP ;
De Bernardi, MA ;
Brooker, G ;
Mocchetti, I .
JOURNAL OF NEUROSCIENCE, 2001, 21 (09) :3104-3112
[6]   Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis [J].
Bachis, Alessia ;
Aden, Sadia A. ;
Nosheny, Rachel L. ;
Andrews, Peter M. ;
Mocchetti, Italo .
JOURNAL OF NEUROSCIENCE, 2006, 26 (25) :6771-6780
[7]   Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in cholinergic and dopaminergic neurons [J].
Banisadr, G ;
Fontanges, P ;
Haour, F ;
Kitabgi, P ;
Rostène, W ;
Parsadaniantz, SM .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2002, 16 (09) :1661-1671
[8]   Chemokine receptors as HIV-1 coreceptors: Roles in viral entry, tropism, and disease [J].
Berger, EA ;
Murphy, PM ;
Farber, JM .
ANNUAL REVIEW OF IMMUNOLOGY, 1999, 17 :657-700
[9]   CXCR4-activated astrocyte glutamate release via TNFa: amplification by microglia triggers neurotoxicity [J].
Bezzi, P ;
Domercq, M ;
Brambilla, L ;
Galli, R ;
Schols, D ;
De Clercq, E ;
Vescovi, A ;
Bagetta, G ;
Kollias, G ;
Meldolesi, J ;
Volterra, A .
NATURE NEUROSCIENCE, 2001, 4 (07) :702-710
[10]   Contribution of proteoglycans to human immunodeficiency virus type 1 brain invasion [J].
Bobardt, MD ;
Salmon, P ;
Wang, LC ;
Esko, JD ;
Gabuzda, D ;
Fiala, M ;
Trono, D ;
Van der Schueren, B ;
David, G ;
Gallay, PA .
JOURNAL OF VIROLOGY, 2004, 78 (12) :6567-6584