Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.
Doitsh, Gilad 1,4; Galloway, Nicole L. K. 1,4; Geng, Xin 1,4; Yang, Zhiyuan 1; Monroe, Kathryn M. 1; Zepeda, Orlando 1; Hunt, Peter W. 2; Hatano, Hiroyu 2; Sowinski, Stefanie 1; Munoz-Arias, Isa 1; Greene, Warner C. 1,2,3
[Article] Nature. 505(7484):509-514, January 23, 2014.

(Format: HTML, PDF)

: The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1[beta], are released. This death pathway thus links the two signature events in HIV infection-CD4 T-cell depletion and chronic inflammation-and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.

(C) 2014 Nature Publishing Group