Dysfunctional HIV-Specific CD8+ T Cell Proliferation Is Associated with Increased Caspase-8 Activity and Mediated by Necroptosis

• HIV-specific CD8+ T cells from progressors have upregulated caspase-8 activity
• Increased caspase-8 activity correlates with impaired proliferative capacity
• Stimulation of progressor HIV-specific CD8+ T cells results in necrotic cell death
• Blockade of necroptosis rescues progressor HIV-specific CD8+ T cell proliferation

SummaryDecreased HIV-specific CD8+ T cell 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+ T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8+ T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8+ T cells 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. In vitro necroptosis blockade rescued HIV-specific CD8+ T cell 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+ T cell proliferation through activation of necroptosis and increased cell death.