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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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Infected CD4 Elimination (ICE) inversely correlates with plasma SIV RNA levels in SIV-infected rhesus macaques.Red dots represent LTNP/EC (n = 11). Blue dots represent progressors (n = 11). Statistical analysis was performed by the Spearman rank method.
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ppat-1003195-g003: Infected CD4 Elimination (ICE) inversely correlates with plasma SIV RNA levels in SIV-infected rhesus macaques.Red dots represent LTNP/EC (n = 11). Blue dots represent progressors (n = 11). Statistical analysis was performed by the Spearman rank method.

Mentions: We found a strong correlation between delivery of active GrB to SIV-infected targets from stimulated CD8+ T cells and ICE (r = 0.89, p<0.001; Figure 2C) consistent with prior work in humans [12]–[14]. This correlation remained strong when the SIV-negative animal was excluded from the analysis (r = 0.87, p<0.001). In addition, plasma SIV RNA levels were inversely correlated with ICE (r = −0.57, p = 0.01; Figure 3). In a post-hoc analysis, we excluded the animals whose target cells did not undergo depletion of human feeders and at the same time had moderately high GrB background. These macaques (A94, 977Z, A98, C114) represented 3 of the 4 animals that were misclassified. The median differences in the cytotoxic responses between LTNP/EC and progressors increased: GrB target cell activity, 47.1% [20.9–70.8%] versus 21.8% [4.9%–46.5%] (p = 0.02) and ICE, 70.8% [22.0–77.3%] versus 22.1% [0.0–43.5%], respectively (p = 0.002). Additionally, the correlation coefficient comparing SIV RNA levels with ICE values increased (r = −0.63, p = 0.01; data not shown).


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)

Infected CD4 Elimination (ICE) inversely correlates with plasma SIV RNA levels in SIV-infected rhesus macaques.Red dots represent LTNP/EC (n = 11). Blue dots represent progressors (n = 11). Statistical analysis was performed by the Spearman rank method.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1003195-g003: Infected CD4 Elimination (ICE) inversely correlates with plasma SIV RNA levels in SIV-infected rhesus macaques.Red dots represent LTNP/EC (n = 11). Blue dots represent progressors (n = 11). Statistical analysis was performed by the Spearman rank method.
Mentions: We found a strong correlation between delivery of active GrB to SIV-infected targets from stimulated CD8+ T cells and ICE (r = 0.89, p<0.001; Figure 2C) consistent with prior work in humans [12]–[14]. This correlation remained strong when the SIV-negative animal was excluded from the analysis (r = 0.87, p<0.001). In addition, plasma SIV RNA levels were inversely correlated with ICE (r = −0.57, p = 0.01; Figure 3). In a post-hoc analysis, we excluded the animals whose target cells did not undergo depletion of human feeders and at the same time had moderately high GrB background. These macaques (A94, 977Z, A98, C114) represented 3 of the 4 animals that were misclassified. The median differences in the cytotoxic responses between LTNP/EC and progressors increased: GrB target cell activity, 47.1% [20.9–70.8%] versus 21.8% [4.9%–46.5%] (p = 0.02) and ICE, 70.8% [22.0–77.3%] versus 22.1% [0.0–43.5%], respectively (p = 0.002). Additionally, the correlation coefficient comparing SIV RNA levels with ICE values increased (r = −0.63, p = 0.01; data not shown).

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