RESUMO
OBJECTIVES: To examine the relation of circulating cytokines and cytokine antagonists to the progression of human immunodeficiency virus type 1 (HIV-1) disease. DESIGN: Cross-sectional analysis. SETTING: An ambulatory acquired immunodeficiency syndrome (AIDS) research clinic in Kinshasa, Zaire. PATIENTS: 48 women with AIDS, 51 women with HIV infection who were clinically asymptomatic, and 11 female controls who did not have HIV infection, all from Zaire. MEASUREMENTS: Plasma levels of interleukin-1beta, tumor necrosis factor-alpha (TNF-alpha), interleukin-6, interleukin-8, interferon-gamma, interleukin-1beta receptor antagonist (interleukin-1Ra), and TNF soluble receptor p55 (TNFsRp55) were assayed by specific radioimmunoassays. Plasma levels of interferon-gamma were assayed by commercial enzyme-linked immunosorbent assay. The Wilcoxon rank-sum test was used to assess the significance of mean and median differences between groups. RESULTS: Of the 48 patients with AIDS, circulating interleukin-1beta was detected in 2, TNF-alpha in 4, interleukin-6 in 3, and interleukin-8 in 12. None of these factors were seen in any of the 11 controls. Median values of interleukin-1beta (320 pg/mL), TNF-alpha (210 pg/mL), and interleukin-8 (750 pg/mL) were elevated in HIV-infected asymptomatic patients compared with patients with AIDS (2-, 2.6-, and 18.7-fold higher, respectively; P < 0.001). Interleukin-1Ra and TNFsRp55 levels were substantially higher than interleukin-1beta and TNF-alpha levels in HIV-infected asymptomatic patients (73- and 14-fold, respectively) and were higher than those in patients with AIDS (17.8- and 1.74-fold, respectively). CONCLUSION: High circulating levels of the proinflammatory cytokines interleukin-1beta and TNF-alpha, combined with an excess of their natural inhibitors interleukin-1Ra and TNF-sRp55, were seen in clinically asymptomatic HIV-1-positive African women but not in African women with AIDS or in HIV-negative controls. Circulating cytokine antagonists may play a clinical role in modulating cytokine-associated symptoms in the early phases of HIV infection.
PIP: At an outpatient AIDS research clinic in Kinshasa, Zaire, physicians conducted a medical examination and took blood samples from 48 women with AIDS, 51 women with asymptomatic HIV-1 infection, and 11 healthy HIV-1 seronegative women to study the relationship of circulating cytokines and cytokine antagonists to the progression of HIV-1 infection. Asymptomatic HIV-1-infected women had higher levels of the cytokines interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) than AIDS cases and controls (320 vs. 156 pg/ml, p 0.001, and 210 vs. 78 pg/ml, p 0.001, respectively) and even higher levels of interleukin-1Ra and TNFsRp55 (both natural cytokine antagonists) (4300 vs. 100 pg/ml, p 0.001; and 12,500 vs. 1450 for the AIDS group [p 0.0001] and 950 for controls [p 0.001]). The high levels of the two proinflammatory cytokines in asymptomatic HIV-1 infected women suggests that the high levels of antagonist cytokines blocked the clinical effects of interleukin-1beta and TNF-alpha. 46 AIDS patients had no detectable interleukin-1beta. 42 AIDS patients had no detectable TNF-alpha. The lack of cytokines in most AIDS patients suggests that persons in end-stage HIV-1 disease have a limited capacity to synthesize cytokines, perhaps depleting the remaining cytokine-producing central and peripheral lymphoid tissues. Asymptomatic HIV-1-infected women also had higher levels of interleukin-8 than AIDS cases and controls (750 vs. 40 pg/ml; p 0.001). 11 of the 13 highest values of interferon-gamma (11 pg/ml) belonged to AIDS patients rather than asymptomatic HIV-1-infected cases (p = 0.005). In the last 2 months, AIDS patients with detectable interferon-gamma had fever of longer duration than those with no interferon-gamma (17 vs. 9 days, p = 0.05), indicating that AIDS cases with interferon-gamma were still capable of responding to inflammatory stimuli. These findings suggest that cytokine antagonists may modulate cytokine-associated symptoms in the early phases of HIV-1 infection.
