Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4

Espert et al., J. Clin. Invest. 116 : 2161-2172 (2006)

Speaker: 張家綸                                                    Time: 13:10~14:00; Oct. 18, 2006

Commentator: 王憲威 老師                              Place: Room 601

Abstract

Acquired immunodeficiency syndrome (AIDS) is a worldwide disease caused by human immunodeficiency virus (HIV) infection. The development of AIDS in HIV-infected patients is characterized by a progressive decline in the number of CD4⁺ T cells. In particular, a bystander effect induced by HIV-1 envelope glycoprotein (Env) gp120 and gp41 expressed on infected cells caused substantial death of uninfected CD4⁺ T cells, especially apoptosis, which is one of features linked to immunodeficiency ¹. Macroautophagy, herein referred to as autophagy, is a conservedlysosomal catalytic process for turning over of macromolecules and organelles in eukaryotic cells². Besides its role in cell survival, several studies suggest that autohpagy also participates in the cell death process. The authors demonstrated that autophagy and accumulation of Beclin 1 was induced in the uninfected CD4⁺ T cells while cocultured with transfected or HIV-infected cells which expressed HIV Env protein. Similar phenomena were observed in a T cell line and in transfected HEK.293 cells which expressed both wild-type CXCR4 and a truncated form of CD4. All together, it suggests that autophagy induced in uninfected CD4⁺ T cells was through interaction of Env with CXCR4. Finally, the study demonstrated that blockage of Env-mediated autophagy at different steps, by either drugs (3-methyladenine and bafilomycin A1) or siRNAs specific for Beclin 1/Atg6 and Atg7 genes, totally inhibited apoptosis. Furthermore, uninfected CD4⁺ T cells still underwentEnv-mediated cell death with autophagic features when apoptosis was inhibited by pan-caspase inhibitor, z-VAD. In conclusion, these results suggest that HIV-infected cells can induce autophay in uninfected CD4⁺ T cells via contact of Env with CXCR4, and the process was necessary for apoptosis, a mechanism most likely contributing to immunodeficiency.

References

1.      Ahr B., Robert-Hebmann V., Devaux C., and Baird-Piechaczyk M. Apoptosis of uninfected cells induced by HIV envelope glycoproteins. Retrovirology. 1: 1-12 (2004).

2.      Levine B., and Yuan J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115: 2679-2688 (2005).