Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques

Daniel Mendoza, Stephen A. Migueles, Julia E. Rood, Bennett Peterson, Sarah Johnson, Nicole Doria-Rose, Douglas Schneider, Eva Rakasz, Matthew T. Trivett, Charles M. Trubey, Vicky Coalter, Claire W. Hallahan, David Watkins, Genoveffa Franchini, Jeffrey D. Lifson, Mark Connors

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18 Scopus citations

Abstract

Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8+ T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4+ T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4+ T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0-91.7%] vs. 23.7% [0.0-58.0%], p = 0.002). In addition, significant correlations between ICE and viral load (r = -0.57, p = 0.01), and between granzyme B delivery and ICE (r = 0.89, p<0.001) were observed. Furthermore, the CD8+ T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (p = 0.004). These findings support that greater lytic granule loading of virus-specific CD8+ T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated.

Original languageEnglish
Article numbere1003195
JournalPLoS Pathogens
Volume9
Issue number2
DOIs
StatePublished - Feb 1 2013

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ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Mendoza, D., Migueles, S. A., Rood, J. E., Peterson, B., Johnson, S., Doria-Rose, N., Schneider, D., Rakasz, E., Trivett, M. T., Trubey, C. M., Coalter, V., Hallahan, C. W., Watkins, D., Franchini, G., Lifson, J. D., & Connors, M. (2013). Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques. PLoS Pathogens, 9(2), [e1003195]. https://doi.org/10.1371/journal.ppat.1003195