title: M- and T-tropic HIVs promote apoptosis in rat neurons.
abstract: 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.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Research Building, Room EP04, Box 571464, Washington, DC 20057, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bachis
authors.forename: Francesca
authors.initials: F
authors.lastname: Biggio
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
authors.forename: Italo
authors.initials: I
authors.lastname: Mocchetti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D016655:HIV Core Protein p24 / Q000096:biosynthesis / Q000235:genetics; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis / Q000235:genetics; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D017628:Microglia / Q000821:virology; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000502:physiology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D007202:Indicators and Reagents; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D053148:Caspase 3