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Membrane expression of HIV envelope glycoproteins triggers apoptosis in CD4 cells
A G Laurent-Crawford1, B Krust, Y Rivière
1Institut Pasteur, Department of AIDS and Retroviruses, UA CNRS 1157, Paris, France.
Insights
HIV-induced apoptosis in CD4+ lymphocytes is triggered by the gp120-gp41 envelope glycoproteins, not syncytia formation. Viral replication and expression of the HIV env gene are necessary for this programmed cell death.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human Immunodeficiency Virus (HIV) infection leads to CD4+ lymphocyte depletion, a hallmark of AIDS.
- The cytopathic effects of HIV, including programmed cell death (apoptosis), are crucial to understand viral pathogenesis.
Purpose of the Study:
- To elucidate the specific mechanism by which HIV induces apoptosis in CD4+ lymphocytes.
- To differentiate between apoptosis induction and syncytia formation during HIV infection.
Main Methods:
- Investigating apoptosis induction by HIV envelope glycoproteins (gp120-gp41) and CD4 receptor interaction.
- Utilizing monoclonal antibodies against CD4 and gp41 to dissect the roles of these molecules.
- Expressing the HIV env gene in CD4+ T cell lines to assess its direct effect on apoptosis.
Main Results:
- Apoptosis is triggered by the cell membrane expression of mature HIV envelope glycoproteins (gp120-gp41) interacting with CD4 receptors.
- Viral replication is necessary to produce the gp120-gp41 complex; viral entry alone does not induce apoptosis.
- Expression of the HIV env gene alone is sufficient to induce apoptosis in CD4+ T cells.
- Apoptosis, unlike syncytia formation, can be suppressed by a CD4 antibody that doesn't block gp120 binding.
- Single-cell apoptosis occurs independently of syncytia formation, as shown by gp41 antibody treatment.
Conclusions:
- HIV-induced apoptosis in CD4+ lymphocytes is a specific event mediated by the gp120-gp41 heterodimer complex.
- Programmed cell death is initiated by the interaction of viral envelope glycoproteins with CD4 receptors on metabolically active cells.
- Apoptosis is a distinct mechanism from syncytia formation and represents a direct consequence of HIV envelope glycoprotein activity.
Abstract:
The cytopathic effect of HIV-1 and HIV-2 in CD4+ lymphocytes has been shown to be associated with apoptosis or programmed cell death. Using different experimental conditions, we demonstrate here that apoptosis is triggered by cell membrane expression of the mature HIV envelope glycoproteins, gp120-gp41 complex, and their interaction with CD4 receptor molecules. Viral entry alone did not induce apoptosis but virus replication was required in order to produce the gp120-gp41 complex. Indeed, expression of the HIV env gene alone in the CD4+ T cell line (CEM) was sufficient for the induction of apoptosis. In general, syncytium formation and apoptosis induction were closely associated as both events require functional envelope glycoproteins and CD4 molecules. Nevertheless, apoptosis but not syncytium formation was suppressed by a monoclonal antibody against CD4 that does not affect gp120 binding. Furthermore, single-cell killing by apoptosis was observed in infected cell cultures treated with a monoclonal antibody against gp41, which completely abolishes the formation of syncytia. These results indicate that apoptosis is not the consequence of toxic effects induced by the formation of syncytia but is triggered by the HIV envelope glycoproteins. Therefore, cell death during HIV infection in CD4+ lymphocyte cultures is due to a specific event triggered by the gp120-gp41 heterodimer complex programming death in metabolically active cells.