Mechanisms of CD4 T-cell depletion triggered by HIV-1 viral proteins

Infection with HIV-1 leads to progressive CD4 T-cell death, resulting in AIDS development. The mechanisms that trigger this CD4 T-cell death are still not fully understood, but a lot of data indicates that apoptosis plays a major role in this cell demise. Both infected and uninfected CD4 T-cells can die during HIV-1 infection by different cell-death pathways, but HIV-1-induced, bystander, CD4 T-cell killing is now recognized as central to immunodeficiency. The HIV-1 directly modulates CD4 T-cell death using multiple different strategies in which several viral proteins have an essential role. Recent data demonstrate that relationships can exist between the three main types of programmed cell death, i.e. apoptosis, autophagic programmed cell death, and necrosis-like programmed cell death. Almost nothing is currently known about the role of necrosis-like programmed cell death in CD4 T-cell death induced by the viral proteins, but a very recent study demonstrates that autophagy is needed to trigger apoptosis of bystander CD4 T-cells, further increasing the level of complexity of this pathology. This review presents an overview of the major types of programmed cell death and details the mechanisms by which the HIV-1 viral proteins control both infected and uninfected CD4 T-cell death.