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Cytotoxic capacity of SIV-specific CD8(+) T cells against primary autologous targets correlates with immune control in SIV-infected rhesus macaques.

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 - PLoS Pathog. (2013)

Bottom Line: 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 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.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.

View Article: PubMed Central - PubMed

Affiliation: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

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SIV-specific CD8+ T cells from LTNP/EC mediate greater lysis of SIV-infected CD4+ T-cell targets compared with progressors.GrB target cell activity (A) and infected CD4 elimination (ICE) (B) are shown for LTNP/EC (n = 10, GrB target cell activity; n = 11, ICE) and progressors (n = 11). Horizontal bars represent the median values. C. Correlation between ICE and GrB target cell activity (n = 22) was determined by the Spearman rank method. Red, blue and cyan dots represent LTNP/EC, progressors and one SIV-uninfected animal, respectively.
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ppat-1003195-g002: SIV-specific CD8+ T cells from LTNP/EC mediate greater lysis of SIV-infected CD4+ T-cell targets compared with progressors.GrB target cell activity (A) and infected CD4 elimination (ICE) (B) are shown for LTNP/EC (n = 10, GrB target cell activity; n = 11, ICE) and progressors (n = 11). Horizontal bars represent the median values. C. Correlation between ICE and GrB target cell activity (n = 22) was determined by the Spearman rank method. Red, blue and cyan dots represent LTNP/EC, progressors and one SIV-uninfected animal, respectively.

Mentions: In comparisons between LTNP/EC and progressors, differences in the median delivery of active GrB to SIV-infected targets did not achieve statistical significance (40.8% [20.9–70.8%] versus 24% [4.9–48.5%], respectively, p = 0.06, Figure 2A). In contrast, the median ICE of LTNP/EC was significantly greater than that of progressors (67.3% [22.0–91.7%] versus 23.7% [0.0–58%], respectively, p = 0.002, Figure 2B). Nearly all of the target cells killed in the 1-hour assay based on light scatter characteristics were GrB substrate positive (data not shown), as observed in humans [12]–[14]. It is noteworthy that in 2 of the 3 LTNP/EC, low cytotoxic responses were attributable to higher backgrounds in samples measured prior to adopting routine depletion of human feeder cells. In addition, one progressor with moderately elevated background in the GrB assay also had a high ICE response in the range of LTNP/EC. Of note, this progressor had been an LTNP/EC for 9 years, but was exhibiting loss of control with higher SIV RNA levels at the time samples were obtained for use in these experiments.


Cytotoxic capacity of SIV-specific CD8(+) T cells against primary autologous targets correlates with immune control in SIV-infected rhesus macaques.

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 - PLoS Pathog. (2013)

SIV-specific CD8+ T cells from LTNP/EC mediate greater lysis of SIV-infected CD4+ T-cell targets compared with progressors.GrB target cell activity (A) and infected CD4 elimination (ICE) (B) are shown for LTNP/EC (n = 10, GrB target cell activity; n = 11, ICE) and progressors (n = 11). Horizontal bars represent the median values. C. Correlation between ICE and GrB target cell activity (n = 22) was determined by the Spearman rank method. Red, blue and cyan dots represent LTNP/EC, progressors and one SIV-uninfected animal, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585127&req=5

ppat-1003195-g002: SIV-specific CD8+ T cells from LTNP/EC mediate greater lysis of SIV-infected CD4+ T-cell targets compared with progressors.GrB target cell activity (A) and infected CD4 elimination (ICE) (B) are shown for LTNP/EC (n = 10, GrB target cell activity; n = 11, ICE) and progressors (n = 11). Horizontal bars represent the median values. C. Correlation between ICE and GrB target cell activity (n = 22) was determined by the Spearman rank method. Red, blue and cyan dots represent LTNP/EC, progressors and one SIV-uninfected animal, respectively.
Mentions: In comparisons between LTNP/EC and progressors, differences in the median delivery of active GrB to SIV-infected targets did not achieve statistical significance (40.8% [20.9–70.8%] versus 24% [4.9–48.5%], respectively, p = 0.06, Figure 2A). In contrast, the median ICE of LTNP/EC was significantly greater than that of progressors (67.3% [22.0–91.7%] versus 23.7% [0.0–58%], respectively, p = 0.002, Figure 2B). Nearly all of the target cells killed in the 1-hour assay based on light scatter characteristics were GrB substrate positive (data not shown), as observed in humans [12]–[14]. It is noteworthy that in 2 of the 3 LTNP/EC, low cytotoxic responses were attributable to higher backgrounds in samples measured prior to adopting routine depletion of human feeder cells. In addition, one progressor with moderately elevated background in the GrB assay also had a high ICE response in the range of LTNP/EC. Of note, this progressor had been an LTNP/EC for 9 years, but was exhibiting loss of control with higher SIV RNA levels at the time samples were obtained for use in these experiments.

Bottom Line: 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 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.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.

View Article: PubMed Central - PubMed

Affiliation: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus