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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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

Fingerprint

Simian Immunodeficiency Virus
Macaca mulatta
T-Lymphocytes
Virus Diseases
Granzymes
HIV Infections
RNA-Directed DNA Polymerase
Viral RNA
Macaca
Virus Replication
Viral Load
Primates
Immunity
Vaccines
Clone Cells
HIV
Viruses

ASJC Scopus subject areas

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

Cite this

Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques. / Mendoza, Daniel; Migueles, Stephen A.; Rood, Julia E.; Peterson, Bennett; Johnson, Sarah; Doria-Rose, Nicole; Schneider, Douglas; Rakasz, Eva; Trivett, Matthew T.; Trubey, Charles M.; Coalter, Vicky; Hallahan, Claire W.; Watkins, David; Franchini, Genoveffa; Lifson, Jeffrey D.; Connors, Mark.

In: PLoS Pathogens, Vol. 9, No. 2, e1003195, 01.02.2013.

Research output: Contribution to journalArticle

Mendoza, D, Migueles, SA, Rood, JE, Peterson, B, Johnson, S, Doria-Rose, N, Schneider, D, Rakasz, E, Trivett, MT, Trubey, CM, Coalter, V, Hallahan, CW, Watkins, D, Franchini, G, Lifson, JD & 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, vol. 9, no. 2, e1003195. https://doi.org/10.1371/journal.ppat.1003195
Mendoza, Daniel ; Migueles, Stephen A. ; Rood, Julia E. ; Peterson, Bennett ; Johnson, Sarah ; Doria-Rose, Nicole ; Schneider, Douglas ; Rakasz, Eva ; Trivett, Matthew T. ; Trubey, Charles M. ; Coalter, Vicky ; Hallahan, Claire W. ; Watkins, David ; Franchini, Genoveffa ; Lifson, Jeffrey D. ; Connors, Mark. / Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques. In: PLoS Pathogens. 2013 ; Vol. 9, No. 2.
@article{0a5c73f0073643688e6f411c70d7a304,
title = "Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques",
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.",
author = "Daniel Mendoza and Migueles, {Stephen A.} and Rood, {Julia E.} and Bennett Peterson and Sarah Johnson and Nicole Doria-Rose and Douglas Schneider and Eva Rakasz and Trivett, {Matthew T.} and Trubey, {Charles M.} and Vicky Coalter and Hallahan, {Claire W.} and David Watkins and Genoveffa Franchini and Lifson, {Jeffrey D.} and Mark Connors",
year = "2013",
month = "2",
day = "1",
doi = "10.1371/journal.ppat.1003195",
language = "English",
volume = "9",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques

AU - Mendoza, Daniel

AU - Migueles, Stephen A.

AU - Rood, Julia E.

AU - Peterson, Bennett

AU - Johnson, Sarah

AU - Doria-Rose, Nicole

AU - Schneider, Douglas

AU - Rakasz, Eva

AU - Trivett, Matthew T.

AU - Trubey, Charles M.

AU - Coalter, Vicky

AU - Hallahan, Claire W.

AU - Watkins, David

AU - Franchini, Genoveffa

AU - Lifson, Jeffrey D.

AU - Connors, Mark

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84879077369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879077369&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1003195

DO - 10.1371/journal.ppat.1003195

M3 - Article

C2 - 23468632

AN - SCOPUS:84879077369

VL - 9

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 2

M1 - e1003195

ER -