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

Gaurav D. Gaiha, Kevin J. McKim, Matthew Woods, Thomas Pertel, Janine Rohrbach, Natasha Barteneva, Christopher R. Chin, Dongfang Liu, Damien Z. Soghoian, Kevin Cesa, Shannon Wilton, Michael T. Waring, Adam Chicoine, Travis Doering, E. John Wherry, Daniel E. Kaufmann, Mathias Lichterfeld, Abraham L. Brass, Bruce D. Walker

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29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1001-1012
Number of pages12
JournalImmunity
Volume41
Issue number6
DOIs
Publication statusPublished - Dec 18 2014

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Gaiha, G. D., McKim, K. J., Woods, M., Pertel, T., Rohrbach, J., Barteneva, N., Chin, C. R., Liu, D., Soghoian, D. Z., Cesa, K., Wilton, S., Waring, M. T., Chicoine, A., Doering, T., Wherry, E. J., Kaufmann, D. E., Lichterfeld, M., Brass, A. L., & Walker, B. D. (2014). Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. Immunity, 41(6), 1001-1012. https://doi.org/10.1016/j.immuni.2014.12.011