HIV patients treated with low-dose prednisolone exhibit lower immune activation than untreated patients

Abstract

Background: HIV-associated general immune activation is a strong predictor for HIV disease progression, suggesting that chronic immune activation may drive HIV pathogenesis. Consequently, immunomodulating agents may decelerate HIV disease progression.

Methods: In an observational study, we determined immune activation in HIV patients receiving low-dose (5 mg/day) prednisolone with or without highly-active antiretroviral therapy (HAART) compared to patients without prednisolone treatment. Lymphocyte activation was determined by flow cytometry detecting expression of CD38 on CD8(+) T cells. The monocyte activation markers sCD14 and LPS binding protein (LBP) as well as inflammation markers soluble urokinase plasminogen activated receptor (suPAR) and sCD40L were determined from plasma by ELISA.

Results: CD38-expression on CD8+ T lymphocytes was significantly lower in prednisolone-treated patients compared to untreated patients (median 55.40% [percentile range 48.76-67.70] versus 73.34% [65.21-78.92], p = 0.0011, Mann-Whitney test). Similarly, we detected lower levels of sCD14 (3.6 μg/ml [2.78-5.12] vs. 6.11 μg/ml [4.58-7.70]; p = 0.0048), LBP (2.18 ng/ml [1.59-2.87] vs. 3.45 ng/ml [1.84-5.03]; p = 0.0386), suPAR antigen (2.17 μg/ml [1.65-2.81] vs. 2.56 μg/ml [2.24-4.26]; p = 0.0351) and a trend towards lower levels of sCD40L (2.70 pg/ml [1.90-4.00] vs. 3.60 pg/ml [2.95-5.30]; p = 0.0782). Viral load in both groups was similar (0.8 × 105 ng/ml [0.2-42.4 × 105] vs. 1.1 × 105 [0.5-12.2 × 105]; p = 0.3806). No effects attributable to prednisolone were observed when patients receiving HAART in combination with prednisolone were compared to patients who received HAART alone.

Conclusions: Patients treated with low-dose prednisolone display significantly lower general immune activation than untreated patients. Further longitudinal studies are required to assess whether treatment with low-dose prednisolone translates into differences in HIV disease progression.

Figure 1

Prednisolone medication in untreated HIV infection is associated with lower CD8+ T cell activation. Whole blood from donors of different treatment groups was stained with fluorescent dye-coupled anti-CD3, anti-CD8 and anti-CD38 antibodies. Cells were analyzed by flow cytometry after erythrocyte lysis. Lymphocytes were gated in a FSC/SSC scatter. CD3+/CD8+ cells from the lymphocyte gate were scored as CD8+ T cells, CD3+/CD8- cells were scored as CD4+ T cells. Horizontal bars represents medians. Statistical analysis was performed using a Mann-Whitney U test. A: Percentage of CD8+ T cells expressing CD38. B: Percentage of CD4+ T cells expressing CD38

Figure 2

Prednisolone medication in untreated HIV infection is associated with lower monocyte activation. sCD14 and LBP concentrations were determined by ELISA from plasma from donors of different treatment groups. Horizontal bars represents medians. Statistical analysis was performed using a Mann-Whitney U test. A: Plasma concentrations of sCD14. B: Plasma concentrations of LBP.

Figure 3

Prednisolone medication in untreated HIV infection is associated with lower inflammation. Concentrations of suPAR and sCD40L were determined by ELISA from plasma from donors of different treatment groups. Horizontal bars represents medians. Statistical analysis was performed using a Mann-Whitney test U-test. A: suPAR. B: sCD40L.

Figure 4

The influence of prednisolone on CD4 counts, CD4/CD8 ratio and naïve T cells. CD4 counts and CD4/CD8 ratio were determined from blood samples by routine diagnostic. Whole blood from donors of different treatment groups was stained with fluorescent dye-coupled anti-CD3, anti-CD4, anti-CD62L and anti-CD45RA antibodies. Cells were analyzed by flow cytometry after erythrocyte lysis. Lymphocytes were gated in a FSC/SSC scatter. CD3+/CD4+/CD62L+/CD45RA cells from the lymphocyte gate were scored as naïve CD4+ T cells, CD3+/CD4-/CD62L+/CD45RA cells were scored as naïve CD8+ T cells. Horizontal bars represent medians. Statistical analysis was performed using a Mann-Whitney test. A: absolute CD4+ T cell counts. B: CD4/CD8 T cell ratio. C: percentage of naïve CD8+ T lymphocytes. D: percentage of naïve CD4+ T lymphocytes.