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A correlate of HIV-1 control consisting of both innate and adaptive immune parameters best predicts viral load by multivariable analysis in HIV-1 infected viremic controllers and chronically-infected non-controllers.

Tomescu C, Liu Q, Ross BN, Yin X, Lynn K, Mounzer KC, Kostman JR, Montaner LJ - PLoS ONE (2014)

Bottom Line: Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05).Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors.Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.

View Article: PubMed Central - PubMed

Affiliation: The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4+ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8+ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters best predicted viral load (R2 = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.

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Predicted versus observed viral load with residuals.(A) A multivariable linear regression analysis using stepwise selection procedure was performed with six target variables (PDC frequency, PDC activation, NK frequency, NK CD16 expression, CD8+ T cell activation, and Pol-specific CD8+ T cell responses) to best predict viral load. The graph of predicted versus observed viral load was used to evaluate the confidence in of model prediction. (B) A graph of residual values versus fitted values of viral load from the stepwise selection procedure to identify parameters that best predict viral load. The residual plot and Breusch-Pagan test were used to examine the heteroskeasticity of the model residuals and an appropriate multivariable linear regression model suggests that residuals are homogeneous.
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pone-0103209-g003: Predicted versus observed viral load with residuals.(A) A multivariable linear regression analysis using stepwise selection procedure was performed with six target variables (PDC frequency, PDC activation, NK frequency, NK CD16 expression, CD8+ T cell activation, and Pol-specific CD8+ T cell responses) to best predict viral load. The graph of predicted versus observed viral load was used to evaluate the confidence in of model prediction. (B) A graph of residual values versus fitted values of viral load from the stepwise selection procedure to identify parameters that best predict viral load. The residual plot and Breusch-Pagan test were used to examine the heteroskeasticity of the model residuals and an appropriate multivariable linear regression model suggests that residuals are homogeneous.

Mentions: Having identified several independent innate and adaptive parameters associated with low viral load in the absence of ART, we generated a multivariable linear regression model to integrate these variables in order to identify the best combination of parameters able to predict viral control. Results of the full multivariable model including all six target variables that were utilized because of their association with viral load (pDC frequency, pDC activation, NK frequency, NK CD16 expression, CD8+ T cell activation, and Pol-specific CD8+ T cell responses) are shown in Table 2. Using stepwise selection procedure, Pol-specific CD8+ T cell responses and pDC frequency were the significant predictors (R2 = 0.5864, p = 0.0021, n = 17) remaining in the final model (Table 3). The graph of predicted versus observed viral load has a strong 45 degree pattern in the data (Figure 3A) with no obvious pattern observed in the residual plot (Figure 3B). However, since the residual plot seemed to slightly expand in the middle, a Breusch-Pagan test was used to further examine the heteroskedasticy. The final model in Table 3 failed to reject the hypothesis that residuals are homoskedastic and we thus concluded that residuals are homogeneous (p = 0.4685). Based on our best model, we observed that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters provided the best predictive value for the observed viral load in HIV-1 infected subjects from our cohort.


A correlate of HIV-1 control consisting of both innate and adaptive immune parameters best predicts viral load by multivariable analysis in HIV-1 infected viremic controllers and chronically-infected non-controllers.

Tomescu C, Liu Q, Ross BN, Yin X, Lynn K, Mounzer KC, Kostman JR, Montaner LJ - PLoS ONE (2014)

Predicted versus observed viral load with residuals.(A) A multivariable linear regression analysis using stepwise selection procedure was performed with six target variables (PDC frequency, PDC activation, NK frequency, NK CD16 expression, CD8+ T cell activation, and Pol-specific CD8+ T cell responses) to best predict viral load. The graph of predicted versus observed viral load was used to evaluate the confidence in of model prediction. (B) A graph of residual values versus fitted values of viral load from the stepwise selection procedure to identify parameters that best predict viral load. The residual plot and Breusch-Pagan test were used to examine the heteroskeasticity of the model residuals and an appropriate multivariable linear regression model suggests that residuals are homogeneous.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4117509&req=5

pone-0103209-g003: Predicted versus observed viral load with residuals.(A) A multivariable linear regression analysis using stepwise selection procedure was performed with six target variables (PDC frequency, PDC activation, NK frequency, NK CD16 expression, CD8+ T cell activation, and Pol-specific CD8+ T cell responses) to best predict viral load. The graph of predicted versus observed viral load was used to evaluate the confidence in of model prediction. (B) A graph of residual values versus fitted values of viral load from the stepwise selection procedure to identify parameters that best predict viral load. The residual plot and Breusch-Pagan test were used to examine the heteroskeasticity of the model residuals and an appropriate multivariable linear regression model suggests that residuals are homogeneous.
Mentions: Having identified several independent innate and adaptive parameters associated with low viral load in the absence of ART, we generated a multivariable linear regression model to integrate these variables in order to identify the best combination of parameters able to predict viral control. Results of the full multivariable model including all six target variables that were utilized because of their association with viral load (pDC frequency, pDC activation, NK frequency, NK CD16 expression, CD8+ T cell activation, and Pol-specific CD8+ T cell responses) are shown in Table 2. Using stepwise selection procedure, Pol-specific CD8+ T cell responses and pDC frequency were the significant predictors (R2 = 0.5864, p = 0.0021, n = 17) remaining in the final model (Table 3). The graph of predicted versus observed viral load has a strong 45 degree pattern in the data (Figure 3A) with no obvious pattern observed in the residual plot (Figure 3B). However, since the residual plot seemed to slightly expand in the middle, a Breusch-Pagan test was used to further examine the heteroskedasticy. The final model in Table 3 failed to reject the hypothesis that residuals are homoskedastic and we thus concluded that residuals are homogeneous (p = 0.4685). Based on our best model, we observed that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters provided the best predictive value for the observed viral load in HIV-1 infected subjects from our cohort.

Bottom Line: Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05).Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors.Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.

View Article: PubMed Central - PubMed

Affiliation: The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4+ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8+ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters best predicted viral load (R2 = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.

Show MeSH
Related in: MedlinePlus