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. 2014 May 15;209(10):1602-12.
doi: 10.1093/infdis/jit801. Epub 2013 Dec 10.

Monocyte Activation by Interferon α Is Associated With Failure to Achieve a Sustained Virologic Response After Treatment for Hepatitis C Virus Infection

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Monocyte Activation by Interferon α Is Associated With Failure to Achieve a Sustained Virologic Response After Treatment for Hepatitis C Virus Infection

Dennis J Hartigan-O'Connor et al. J Infect Dis. .
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Abstract

Background: Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells.

Methods: We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN. We analyzed the variable responses of antigen-presenting cell subsets to drug.

Results: We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR.

Conclusions: These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens.

Keywords: Toll-like receptor 2; activation; dendritic cells; hepatitis C virus; interferon-α; monocytes; ribavirin; sustained virologic response; treatment.

Figures

Figure 1.
Figure 1.
Upregulation of activation markers on myeloid dendritic cells (mDCs) and monocytes after in vitro stimulation with interferon α (IFN-α). A, The expression of CD80 and CD86 on mDCs is shown before (top panels) and after (bottom panels) in vitro stimulation with 400 U/mL IFN-α. Gates shown in this panel and those for CD80 and CD86 in panel B were set on the basis of fluorescence minus one controls [19]. B, The expression of various activation markers on CD14+ monocytes is shown before (top panels) and after (bottom panels) in vitro stimulation with 400 U/mL IFN-α. Gates for major histocompatibility (MHC) class I and class II (HLA-DR) molecules were set so as to maximize differences between the unstimulated and stimulated samples. C, The mean change in expression of activation markers on monocytes after in vitro stimulation with IFN-α. All changes were statistically significant (Table 2). D, The change in expression of activation markers on monocytes, by sustained virologic response (SVR) status. The uncorrected between-group differences shown here were all significant (from left to right, P = .003, .013, .049, .0007, and .002, respectively, by the rank sum test). Abbreviation: MFI, mean fluorescence intensity.
Figure 2.
Figure 2.
Lasso regression of activation markers as predictors of achievement of sustained virologic response. A, Cross-validation of the regression model for mean fluorescence intensity (MFI) variables as the penalty parameter lambda is decreased (abscissa, bottom label) and the number of included variables is correspondingly increased (abscissa, top label). The cross-validated deviance reaches a minimum after inclusion of 3 variables. B, Cross-validation of the regression model for percentage-positive variables. C, Coefficient values in the regression model for MFI variables as the L1 norm (ie, the sum of the absolute values of coefficients) increases (abscissa) and the number of variables with non-0 coefficients correspondingly increases. All MFI variables chosen by the lasso algorithm for inclusion in the model are measures of monocyte activation. This panel shows individual coefficient values. D, Coefficients in the regression model for MFI variables summed by cell type. E, Individual coefficient values in the regression model for percentage-positive variables. F, Coefficients in the regression model for percent positive variables summed by cell type. Abbreviations: mDC, myeloid dendritic cell; MHC, major histocompatibility complex; pDC, plasmacytoid dendritic cell.
Figure 2.
Figure 2.
Lasso regression of activation markers as predictors of achievement of sustained virologic response. A, Cross-validation of the regression model for mean fluorescence intensity (MFI) variables as the penalty parameter lambda is decreased (abscissa, bottom label) and the number of included variables is correspondingly increased (abscissa, top label). The cross-validated deviance reaches a minimum after inclusion of 3 variables. B, Cross-validation of the regression model for percentage-positive variables. C, Coefficient values in the regression model for MFI variables as the L1 norm (ie, the sum of the absolute values of coefficients) increases (abscissa) and the number of variables with non-0 coefficients correspondingly increases. All MFI variables chosen by the lasso algorithm for inclusion in the model are measures of monocyte activation. This panel shows individual coefficient values. D, Coefficients in the regression model for MFI variables summed by cell type. E, Individual coefficient values in the regression model for percentage-positive variables. F, Coefficients in the regression model for percent positive variables summed by cell type. Abbreviations: mDC, myeloid dendritic cell; MHC, major histocompatibility complex; pDC, plasmacytoid dendritic cell.
Figure 3.
Figure 3.
Variable importance by random forest methodology. This chart lists the top 25 most important variables for classification of subjects into groups of those with and those without sustained virologic response (SVR), using classification trees. Monocyte activation in the presence of interferon α (IFN-α), as assessed by CD80 mean fluorescence intensity, is second only to IL28B genotype. Abbreviations: HCV, hepatitis C virus; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; pDC, plasmacytoid dendritic cell.
Figure 4.
Figure 4.
Association of important predictors of sustain virologic response (SVR) with viral load. A, The IL28B CC genotype is associated with higher viral load among subjects not achieving SVR, as previously reported [26]. Note that this association is in contrast to that which might be expected from a genotype associated with clearance. B, Hepatitis C virus (HCV) load is not predictive of in vitro monocyte activation (P = .16, by linear regression). Abbreviation: MFI, mean fluorescence intensity.

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