Evidence for innate immune system activation in HIV type 1-infected elite controllers - PubMed (original) (raw)

Evidence for innate immune system activation in HIV type 1-infected elite controllers

Sonya Krishnan et al. J Infect Dis. 2014 Mar.

Abstract

Background: Elite controllers maintain high CD4(+) T-cell counts and suppress plasma human immunodeficiency virus (HIV) viremia in the absence of antiretroviral therapy (ART). It is unclear whether levels of biomarkers associated with coagulation, monocyte activation, and inflammation, which are linked to HIV-associated mortality, differ among elite controllers, ART recipients with suppressed viremia (plasma HIV type 1 RNA load, <50 copies/mL), and HIV-negative controls.

Methods: A total of 68 elite controllers, 68 ART recipients with suppressed viremia, and 35 HIV-negative participants were evaluated. Levels of biomarkers in cryopreserved plasma were measured by enzyme-linked immunosorbent assay and electrochemiluminescence-based assay. Cryopreserved peripheral blood mononuclear cells were used to assess monocyte phenotype and function and interferon-inducible gene expression (IFIG). Nonparametric testing was used to compare median values among groups.

Results: CD4(+) T-cell counts were similar between elite controllers and HIV-negative controls but significantly lower in ART recipients with suppressed viremia. Levels of C-reactive protein and interleukin 6 were higher and IFIG upregulated in both HIV-positive groups, compared with HIV-negative controls. D-dimer and soluble tissue factor levels were significantly elevated in elite controllers, compared with those in ART recipients with suppressed viremia and HIV-negative controls (P < .01). Monocytes from elite controllers (and ART recipients with suppressed viremia) expressed lower CCR2 and higher CX3CR1 levels than monocytes from HIV-negative controls. In addition, elite controllers had a significantly higher proportion of CD14(++)CD16(+) monocytes, compared with HIV-negative controls.

Conclusion: Elite controllers maintain control of plasma HIV viremia and have evidence of an activated innate immune response.

Keywords: Biomarkers; D-dimer; Elite Controllers; HIV; Monocytes; soluble Tissue Factor.

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Figures

Figure 1.

Figure 1.

Expression of interferon (IFN)–inducible genes in elite controllers, antiretroviral therapy recipients with suppressed viremia, and human immunodeficiency virus (HIV)–negative controls. See Methods for descriptions of participant groups. Gene expression was normalized to HIV-negative controls and 2 housekeeping genes. The asterisks denotes a P value of < .05, compared with HIV-negative controls, and the black bars denote statistically significant differences between the 2 HIV-positive groups by 1-way analysis of variance with corresponding P values as shown. Genes included are those expressing IFN-induced protein with tetratricopeptide repeats (IFIT) 1 and 3, chemokine C-C ligand 5 (CCL5), IFN-induced GTP-binding protein Mx (MX) 1 and 2, 2′-5′-oligoadenylate synthetase 2 (OAS2), signal transducers and activators of transcription 1 (STAT1), and IFN-γ (IFNG).

Figure 2.

Figure 2.

Proportion of CD14++CD16+ (A), CCR2+ (B), and CX3CR1+ (C) monocytes in elite controllers, compared with antiretroviral therapy recipients with suppressed viremia and human immunodeficiency virus (HIV)–negative controls. See Methods for descriptions of participant groups. Comparisons were done between groups by the Mann–Whitney U test. Median values and interquartile ranges are indicated by bars.

Figure 3.

Figure 3.

Proportion of tissue factor (TF)–expressing monocytes (A) and interleukin 1β (IL-1β)–expressing monocytes (B) in response to lipopolysaccharide (LPS) stimulation in elite controllers, compared with antiretroviral therapy (ART) recipients with suppressed viremia and HIV-negative controls. See Methods for descriptions of participant groups. Peripheral blood mononuclear cells were stimulated for 6 hours with LPS, treated with brefeldin A to block cytokine secretion, and then stained and fixed. Monocytes were gated as HLA-DR+ and lineage negative. Absolute increases in percentage of cells expressing TF (A) and IL-1β (B) in response to LPS stimulation were compared between the 3 groups by the Kruskal-Wallis test and then the Mann–Whitney U test for comparisons between 2 groups. Median values and interquartile ranges are indicated by bars.

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