Dysfunctional HIV-specific CD8⁺ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis

Decreased HIV-specific CD8⁺ Tcell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8⁺ Tcells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8⁺ Tcell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8⁺ Tcells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. Invitro necroptosis blockade rescued HIV-specific CD8⁺ Tcell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8⁺ Tcell proliferation through activation of necroptosis and increased cell death.