Human Immunodeficiency Virus-Induced Interferon-Stimulated Gene Expression Is Associated With Monocyte Activation and Predicts Viral Load

Abstract

Background: Chronic immune activation is one of the hallmarks of human immunodeficiency virus (HIV) pathogenesis. Persistent upregulation of interferons (IFNs) and interferon-stimulated genes (ISGs) has previously been associated with chronic immune activation and HIV progression. Here a longitudinal analysis of the IFN and ISG response during HIV infection was performed to gain insights into the ongoing immune activation during HIV infection.

Methods: IFN and ISG levels were determined using quantitative polymerase chain reaction in peripheral blood mononuclear cells of people with HIV at pre-seroconversion, during acute and chronic HIV infection, and during suppressive antiretroviral therapy (ART).

Results: HIV infection induced the expression of a set of 4 ISGs-RSAD2, ISG15, IFI44L, and IFI27-which remained upregulated during chronic infection. This set of ISGs showed no clear correlations with T-cell activation as determined by co-expression of CD38 and HLA-DR. However, a strong correlation with monocyte activation marker soluble CD163 in serum was found. Furthermore, the expression of this ISG cluster was predictive of viral load before ART initiation and, on ART, expression levels normalized to pre-seroconversion levels.

Conclusions: The results presented here suggests that ISG expression is linked to monocyte activation, possibly driven by viral replication.

Keywords: HIV; ISG; immune activation; innate immune response; monocyte.

Figure 1.

Longitudinal interferon (IFN) and interferon-stimulating gene (ISG) expression levels during human immunodeficiency virus (HIV) infection in people with HIV (PWH). Depicted are the IFN and ISG expression levels in PWH before infection with HIV (pre-seroconversion [SC]) and at 3 time points after HIV infection (5–9 months, 2 years, and 6 years post-SC). Expression levels of ISGs were calculated using the 2^–ΔΔCt method relative to controls without HIV. Significant P values, as determined by Friedman analysis of variance test for repeated measurements within an individual followed by Dunn post hoc tests: *P < .05; **P < .01; ***P < .001; ****P < .0001. Abbreviations: ART, antiretroviral therapy; SC, seroconversion; sCD163, soluble CD163.

Figure 2.

Correlograms of interferon (IFN) and interferon-stimulating gene (ISG) expression levels before and during human immunodeficiency virus (HIV) infection. Depicted are the correlations between IFN and ISG expression levels in people with HIV pre-seroconversion (SC; A), 2 years post-SC (B), pre–antiretroviral therapy (ART) (C), and on ART (D). Positive correlations are displayed in blue and negative correlations in red. The color intensity and the size of the circle are proportional to the correlation coefficients. Significant q values, as determined by Pearson correlation and adjusted for false discovery rate: *q < 0.05; **q < 0.01; ***q < 0.001; ****q < 0.0001.

Figure 3.

Correlation between interferon-stimulating genes (ISGs) and biomarkers of human immunodeficiency virus disease progression. Depicted are the correlations between ISGs and T-cell activation, T-cell counts, and viral load at pre-seroconversion (SC; A), 6 years after SC (B), and on antiretroviral therapy (ART; C). D, Depicted are the correlations between ISGs and serum markers CXCL10 and soluble CD163 at pre- and post-SC. Positive correlations are displayed in blue and negative correlations in red. The color intensity and the size of the circle are proportional to the correlation coefficients. Significant q values, as determined by Pearson correlation and adjusted for false discovery rate: *q < 0.05; **q < 0.01; ***q < 0.001; ****q < 0.0001.

Figure 4.

Predictive value of interferons (IFNs) and interferon-stimulating gene (ISG) expression for pre–antiretroviral therapy (ART) viral load. Depicted are the β-coefficient and 95% confidence interval (CI) for IFN and ISG expression levels in people with human immunodeficiency virus at 5–9 months post-seroconversion for viral load before the start of ART (pre-ART). All analyses were corrected for age at seroconversion. Significant P values, as determined by linear regression analysis: *P < .05; **P < .01.