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Membrane-expressed HIV envelope glycoprotein heterodimer is a powerful inducer of cell death in uninfected CD4+
A G Laurent-Crawford1, E Coccia, B Krust
1Unité de Virologie et Immunologie cellulaire, UA 1157 CNRS, Institut Pasteur, Paris.
Insights
The HIV envelope proteins gp120 and gp41 can directly induce apoptosis in CD4+ T cells, independent of viral infection. This cell death mechanism is triggered by the interaction of these proteins with the CD4 receptor.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human Immunodeficiency Virus (HIV) infection of CD4+ T cells leads to viral production and apoptosis (programmed cell death).
- This cytopathic effect is observed with various HIV isolates and is triggered by the interaction of the HIV envelope glycoproteins (gp120-gp41) with the CD4 receptor on T cells.
Purpose of the Study:
- To establish an experimental model to induce apoptosis independently of HIV infection.
- To investigate the role of HIV envelope glycoproteins gp120 and gp41 in inducing apoptosis.
Main Methods:
- Transiently transfected HeLa cells expressing the HIV1 env gene were used as effector cells.
- CD4+ MOLT4-T4 T cells served as target cells.
- Mutations in envelope glycoproteins were introduced to assess their impact on CD4 binding and fusion.
Main Results:
- Apoptosis induction requires membrane expression of both gp120 and gp41.
- Point mutations affecting CD4 receptor binding or the fusion process abrogated apoptosis induction.
- A V3 loop mutation inhibiting fusion but not CD4 binding also abrogated apoptosis.
Conclusions:
- The induction of apoptosis is an intrinsic property of the cell membrane-expressed gp120-gp41 complex.
- These findings suggest that apoptosis induction is a key function of HIV env gene products.
Abstract:
HIV infection of CD4+ T cells in culture results in the production of virus and induction of cell killing by apoptosis. Such a cytopathic effect is observed during infection with syncytium-inducing or non-syncytium-inducing HIV isolates. Apoptosis is triggered by the interaction of the cell membrane-expressed HIV envelope glycoprotein heterodimer gp120-gp41 complex (external and transmembrane glycoprotein complex) with the CD4 receptor. Here we demonstrate an experimental model for the induction of apoptosis independent of HIV infection, using transiently transfected HeLa cells with the HIV1 env gene as effector cells and the CD4+ MOLT4-T4 T cells as target cells. Results obtained confirm that the induction of apoptosis requires the membrane expression of the two HIV env gene products, gp120 and gp41. Single amino acid point mutations of the envelope products that affect binding to the CD4 receptor or the fusion process abrogate the capacity of the gp120-gp41 complex to induce apoptosis. Interestingly, a point mutation in the V3 loop which inhibits fusion without affecting CD4 binding also results in the abrogation of apoptosis. These observations indicate that the induction of apoptosis is an intrinsic property of the cell membrane-expressed gp120-gp41 complex, and thus should be considered as one of the functions of HIV env gene products.