HIV’s unkind cut

Sainski et al. reveal how an inactive caspase fragment spawned by HIV infection can still kill T cells.

HIV triggers a precipitous decline in the number of CD4 T cells. One way that the virus slays these cells is by provoking apoptosis. But one aspect of the apoptotic mechanism remains puzzling. The HIV protease trims the apoptosis-promoting cellular enzyme caspase 8. The resulting fragment, known as Casp8p41, is enzymatically inert but nonetheless induces cell death.

Sainski et al. discovered that Casp8p41 binds to a proapoptotic protein called Bak. The researchers determined that caspase 8 carries a domain that fits into a groove on Bak and switches the protein on. However, the C terminus of caspase 8 normally overhangs this domain and prevents it from interacting with Bak. When HIV infects a CD4 T cell, the protease cuts away caspase 8’s C terminus, exposing the Bak-activating domain. Bak molecules can then oligomerize and trigger cell death by spurring mitochondria to become leaky. Mutating two amino acids in the Bak-binding domain made cells less susceptible to viral infection.

The protease inhibitors that are staples of HIV treatment thwart this apoptosis-inducing mechanism by preventing the protease from trimming caspase 8. The study raises the possibility that other viruses or cell-killing pathways might also induce their effects by revealing hidden activator domains in proteins.