Prediction of immune state and viral suppression in HIV-1 infection using IL-6: IFN-γ ratios

Abstract

Introduction: Cytokine dysregulation is a hallmark of HIV infection with a rise in plasma IL-6 largely reported to enhance HIV-1 replication while IFN-γ shows hindrance. Besides, IL-6 inhibits IFN-γ secretion through the STAT3 pathway to aid HIV-1 survival. High IL-6: IFN-γ ratios may thus be linked to HIV-1 survival yet IL-6 and IFN-γ are commonly independently evaluated. This study determined IL-6: IFN-γ ratios as an indicator of HIV-1 immune state and viral suppression. Methodology: A cross-sectional study involving 240 HIV-1 infected people on ART was done. Viral load, CD4 T-cell counts, IL-6 and IFN-γ were assayed and IL-6: IFN-γ ratios calculated. Categorization into viral suppressing (<1000 virus copies), viral non-suppressing (>1000 virus copies), severe immune suppressed (<200 CD4 T-cells) and non-severe immune suppressed (>200 CD4 T-cells) were done. Correlation between HIV-1 viral load and CD4 T-cell counts with IL-6, IFN-γ and IL-6: IFN-γ ratios was established. Comparison of IL-6, IFN-γ and IL-6: IFN-γ ratios across different categories was performed using Welch’s T-test. ROC analysis to determine the accuracy of IL-6, IFN-γ and IL-6: IFN-γ ratios in classification of persons was done. Results: There was no significant correlation between HIV-1 viral load and CD T-cell counts with IL-6, IFN-γ and IL-6 to IFN-γ ratios. But, IL-6 and IL-6 to IFN-γ ratios were raised among viral suppressing compared to the viral non-suppressing patients (p-value: 0.024 and 0.017 respectively) unlike IFN-γ without variation across these categories. However, persons on ART for 6 months had raised IL-6 among the viral non-suppressing compared to those viral suppressing (p-value: 0.005). No variation across CD4 T-cell count categorization was seen. The IL-6, IFN-γ and IL-6 to IFN-γ ratio correctly classified 59%, 41%, 65% of HIV-1 infected persons as viral suppressing or non-suppressing and 51%, 70%, 51% as severe or non-severe immune suppressed respectively. Conclusion: IL-6 to IFN-γ ratios improve the accuracy of independent IL-6 and IFN-γ tests in classification of people living with HIV-1 as viral suppressing or non-suppressing but is not a suitable direct replacement of HIV-1 viral load or CD4 T-cell counts. ART induced IL-6 secretion may preferentially up regulate IFN-γ secretion through stimulation of follicular T-helper cells other than the inhibition through the STAT3 pathway. IL-6 secretion patterns and their influence on IFN-γ among HIV-1 infected persons on ART may fully be understood by reviewing a full cytokine profile and transcription factors in comparison to ART naïve HIV-1 infected persons.