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P Aukrust

Publications and source records attributed to P Aukrust.

At least 19 recordsLinked to original sources
PubMed2000

CXC-chemokines, a new group of cytokines in congestive heart failure--possible role of platelets and monocytes.

OBJECTIVES: The purpose of the present study was to examine the circulating levels of CXC-chemokines in patients with various degree of congestive heart failure (CHF). BACKGROUND: CXC-chemokines may be important mediators in the persistent immune activation observed in CHF patients by activation of circulating neutrophils, T-cells and monocytes and possibly by the recruitment of these cells into the failing myocardium. METHODS: Levels of interleukin (IL)-8, growth-regulated oncogene (GRO) alpha and epithelial neutrophil activating peptide (ENA)-78 were measured both in serum and in platelet-free plasma by enzyme immunoassay in 47 patients with CHF and in 20 healthy controls. RESULTS: (i) CHF patients had significantly elevated levels of all the three CXC-chemokines with IL-8 and GRO alpha showing a gradual increase along with increasing NYHA class. (ii) There was an inverse correlation between IL-8 and left ventricular ejection fraction (EF) and cardiac index (CI). (iii) Both unstimulated and lipopolysaccharide (LPS)-stimulated monocytes from CHF patients released markedly elevated amounts of all three CXC-chemokines. (iv) Platelets from patients with severe CHF were characterised by decreased content of GRO alpha and ENA-78 as well as decreased release of these chemokines upon thrombin receptor stimulation. (v) Activated platelets stimulated peripheral blood mononuclear cells in vitro to enhanced release of IL-8, and neutralising antibodies against ENA-78 inhibited this interaction. CONCLUSIONS: This study demonstrates for the first time elevated levels of CXC-chemokines in CHF, which may be of importance for progression of heart failure. Our findings further suggest that activated monocytes and platelets may contribute to enhanced CXC-chemokine levels in CHF.

Analysis of Variance↗
PubMed2000

Peripheral endothelial dysfunction in heart transplant recipients: possible role of proinflammatory cytokines.

Endothelium-dependent vasodilation in the peripheral circulation may be impaired in heart transplant recipients (HTx rec). Conflicting results have been obtained and the mechanisms involved have not been examined. In the present study, we examined whether long-time survivors of heart transplantation (Tx) show signs of endothelial dysfunction in the peripheral microcirculation, and further investigated the possible role of endothelium-related markers and proinflammatory cytokines in this process. The vasodilatory responses to acetylcholine (Ach) (endothelium-dependent) and sodium nitroprusside (SNP) (endothelium-independent) were evaluated by skin laser-Doppler perfusion measurements in 63 clinically stable HTx rec 6 yr (range 1-13 yr) after Tx, and compared with 20 healthy controls. Ten HTx rec were also followed prospectively with three repeated measurements during the first year after Tx. Plasma von Willebrand factor, big-endothelin (b-ET), and proinflammatory cytokines were measured by enzyme immunoassays. Vascular responses to both Ach and SNP were significantly attenuated in the HTx rec compared with controls. In longitudinal testing, there was a significant reduction in endothelium-dependent vasodilation, but not independent vasodilation from 1 to 12 months after Tx. Plasma levels of vWF and b-ET, as well as levels of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1beta, were all markedly increased in HTx rec. HTx rec responses to Ach were negatively correlated to TNF-alpha levels in plasma (r = -0.39, p < 0.01). Moreover, there was also a significant positive correlation between plasma b-ET and TNF-alpha (r = 0.34, p < 0.01). In the long-term follow-up of HTx rec, endothelial dysfunction is demonstrated by both regulation of blood flow in the skin microcirculation and by raised markers of endothelial activation in plasma. This endothelial dysfunction may be related to enhanced levels of proinflammatory cytokines in these patients.

Acetylcholine↗
PubMed2000

Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection.

Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV-infected patients had raised levels of both IP-10 and IFN-alpha compared with healthy controls (n = 19), with particularly high levels in advanced disease. HAART induced a marked decrease in levels of both IFN-alpha, neopterin and IP-10, though not to normal concentrations. In contrast, IFN-gamma levels were low throughout the study, and not different from controls. While neopterin and IP-10 remained significantly decreased compared with baseline levels throughout the study, IFN-alpha levels returned to baseline at the end of the study. Persistently high IP-10 and IFN-alpha levels were associated with immunological treatment failure and even high baseline levels of IFN-alpha appeared to predict immunological relapse. Furthermore, we found a markedly suppressive effect of exogenously added IFN-alpha on phytohaemagglutinin-stimulated lymphocyte proliferation in both patients and controls, and this suppressive effect seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-alpha in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART.

Anti-HIV Agents↗
PubMed2000

Chemokines and soluble adhesion molecules in renal transplant recipients with cytomegalovirus infection.

Cytomegalovirus (CMV) infection is associated with leucocyte infiltration in various organs, which supports a role for chemokines and adhesion molecules in the pathogenesis of CMV infection. In a prospectively conducted study of renal transplant recipients, 10 patients with CMV disease, five patients with asymptomatic CMV infection and 10 patients who did not have any CMV infection were included. During CMV infection, and in particular during CMV disease, plasma levels of the chemokines IL-8, macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1) and the soluble adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and L-selectin increased and were positively correlated with the degree of CMV pp65 antigenaemia. Furthermore, a decrease in plasma levels of these chemokines and adhesion molecules was observed following ganciclovir therapy in the patients with CMV disease. This could suggest a role for these molecules in the pathogenesis of CMV infection.

Adult↗
PubMed2000

Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses.

BACKGROUND: Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B-cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI. PATIENTS AND METHODS: We analysed plasma vitamin A levels in 20 CVI patients and 16 controls, and examined the relationships between vitamin A and clinical, immunological and metabolic parameters in CVI. In the six CVI patients with the lowest vitamin A levels we also studied the effect of vitamin A supplementation in vivo on several immunological functions in these patients. RESULTS: (i) The majority of CVI patients had decreased vitamin A levels compared with healthy controls, as found in both cross-sectional and longitudinal testing. (ii) Low vitamin A levels were associated with the occurrence of chronic bacterial infections and splenomegaly as well as high neopterin levels. Decreased levels of carrier protein and malabsorption were not observed. (iii) Vitamin A supplementation in patients with low vitamin A levels resulted in increased interleukin-10 (IL-10) and decreased tumour necrosis factor-alpha (TNFalpha) levels, as found in both plasma and monocyte supernatants, possibly favouring anti-inflammatory net effects. (iv) Vitamin A supplementation in vivo also enhanced anti-CD40-stimulated IgG production, serum IgA levels and phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cell (PBMC) proliferation. CONCLUSION: A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.

Adult↗
PubMed2000

The role of the tumor necrosis factor system and interleukin-10 during cytomegalovirus infection in renal transplant recipients.

The effects of cytomegalovirus (CMV) infection on monocyte and T cell activation and the role of the tumor necrosis factor (TNF) system and interleukin (IL)-10 were studied in a prospective study of 25 renal transplant recipients. Ten patients developed CMV disease (group A), 5 developed asymptomatic infection (group B), and 10 did not have CMV infection (group C). During CMV disease (group A), there was evidence of both monocyte and T cell activation. All patients with CMV infection (groups A and B) showed increased activation of the TNF system, concomitant with an increase in plasma levels of IL-10. Patients with CMV disease (group A) had more marked manifestations of TNF activation and more moderate IL-10 increase than patients with asymptomatic CMV infection (group B), reflected in a higher plasma IL-10/TNF-alpha ratio in asymptomatic patients. Thus, the balance between TNF-alpha and IL-10 may be important in the development of CMV infection and CMV-related disease.

Adult↗
PubMed1999

Additive effects of IL-2 and protein kinase A type I antagonist on function of T cells from HIV-infected patients on HAART.

OBJECTIVE: To explore the basis for a possible immunomodulatory combination therapy with IL-2 and agents inhibiting protein kinase A (PKA) type I. DESIGN: Highly active antiretroviral therapy (HAART) has dramatically improved HIV therapy, but fails to eradicate the virus, and the persistence of HIV-associated immunodeficiency demonstrates the need for additional immunomodulating therapies. We have previously shown that hyperactivation of PKA type I inhibits the function of HIV-infected patient T cells. The separate and combined effect of a PKA type I-selective antagonist (Rp-8-Br-cAMPS) and Interleukin (IL)-2 on the function of T cells from HIV-infected patients on HAART was examined. METHODS: The effect of Rp-8-Br-cAMPS on anti-CD3 stimulated proliferation and IL-2 production and the combined effect with exogenous IL-2 was studied in vitro with cells from 13 HIV-infected patients on HAART and six uninfected controls. RESULTS: The PKA type I-selective antagonist improved cell proliferation (median 1.5-fold, maximal 2.8-fold) and IL-2 production (median 1.5-fold, maximal 2.4-fold) in T cells from HIV-infected patients on HAART, but not in controls. The addition of IL-2 enhanced proliferation of T cells from HIV-infected patients (approximately 1.9-fold) and that of controls (approximately 1.4-fold), but IL-2 had no effect at the concentrations produced by treatment with PKA type I antagonist. However, the combined effect of IL-2 and PKA type I antagonist was additive and resulted in a further increase in T-cell proliferation (median 2.5-fold, maximal 5.8-fold), reaching levels comparable with those of uninfected controls in most of the patients. CONCLUSION: Our findings suggest a basis for a novel strategy in treatment of HIV infection by combining IL-2 therapy and treatment modalities counteracting PKA type I activity with HAART.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Possible role of proinflammatory cytokines in heart allograft coronary artery disease.

Transplant coronary artery disease (Tx-CAD) is the main determinant of long-term prognosis after heart transplantation. Immunologic processes may play a central role in the development of Tx-CAD, but the pathogenesis has not been fully clarified. We examined plasma levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL)-1beta and IL-6, and the CC-chemokine macrophage chemoattractant protein-1 (MCP-1) in 62 cardiac allograft recipients undergoing yearly heart catherization with coronary angiography for evaluation of graft disease. In this cross-sectional study, we found significantly increased levels of IL-1beta, IL-6, TNF-alpha, and MCP-1 compared with healthy controls even several years (median 7 years) after transplantation in periods with no intercurrent illness. Although no significant differences were found in plasma levels of IL-1beta and TNF-alpha between patients with (n = 25) and without (n = 37) Tx-CAD, the Tx-CAD group had significantly increased levels of IL-6 and MCP-1 compared with both controls and transplant recipients without Tx-CAD. Increased IL-6 levels compared with controls were found only in patients with Tx-CAD. Finally, while there was no significant relation between Tx-CAD and altered lipid status, the combination of high plasma concentrations of IL-6 or MCP-1 and high low-density lipoprotein cholesterol was strongly associated with increased occurrence of Tx-CAD. These findings indicate that cardiac allograft recipients have a persistent immune activation long term after transplantation. This activation, as particularly reflected in increased MCP-1 and IL-6 levels, may be related to the development of Tx-CAD.

Adult↗
PubMed1999

Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes.

BACKGROUND: The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma. METHODS AND RESULTS: To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow. (1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor-agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis. CONCLUSIONS: This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes.

Acute Disease↗
PubMed1999

CD4+ and CD8+ lymphocytes and HIV RNA in HIV infection: high baseline counts and in particular rapid decrease of CD8+ lymphocytes predict AIDS.

OBJECTIVE: To study the progression of HIV infection in relation to immunological and virological variables with emphasis on the role of CD8+ lymphocytes. DESIGN: Prospective follow-up from October 1991 of patients observed for at least 18 months allowing nucleoside analogue monotherapy. Peripheral CD4+ and CD8+ lymphocyte counts, HIV RNA, and soluble CD8 were analysed by statistics allowing the evaluation of serial data, avoiding time points with concurrent infections. SETTING: Tertiary university clinic. PATIENTS: Forty-nine patients were followed for 52.6 months, baseline CD4+ count of 300 x 10(6)/l, sample interval of 5.9 months (medians). MAIN OUTCOME MEASURES: AIDS, death, and CDC groups B- or C-related events. RESULTS: AIDS developed in 28% of patients. Baseline CD8+ counts above the median were significantly associated with AIDS development; the best Cox model included CD8+ cells and the log10RNA/CD4 ratio. A decline in CD8+ counts relative to baseline most significantly predicted AIDS, along with higher baseline RNA and actual CD4+ counts of less than 200 x 10(6)/l. Levels of soluble CD8 in the blood relative to total CD8+ cells significantly increased in patients developing AIDS. Death occurred in 16% of the patients, and was only predicted by high CD8+ cell counts at baseline. CDC B- and C-related events occurred in 35% of the patients and were best predicted by high baseline CD8+ counts and high RNA levels. CONCLUSIONS: The serial quantitation of CD8+ lymphocytes gave highly significant predictive information on the natural progression of HIV infection in patients with moderate to severe immune deficiency. Our data suggest that the hyperactivation of CD8+ lymphocytes is an important factor leading to a numerical decrease of CD8+ lymphocytes in progressive HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.

Adult↗
PubMed1999

Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency.

The molecular mechanisms underlying the T cell dysfunction often present in common variable immunodeficiency (CVI) are not established. cAMP-dependent protein kinase A type I (PKAI) is an important inhibitor of T cell proliferation after Ag stimulation. We therefore investigated the possibility that activation of PKAI may be involved in the development of T cell dysfunction in CVI. An exogenously added PKAI-selective antagonist (Rp-8-Br-cAMPS) induced a significant increase in anti-CD3-stimulated PBMC proliferation in 20 CVI patients compared with no effect in 15 controls. Purified T cells from 7 CVI patients with strictly defined T cell deficiency had elevated endogenous cAMP levels compared with controls. Treatment of T cells from these CVI patients with Rp-8-bromo-cAMP-phosphorothioate markedly improved anti-CD3-stimulated proliferation (up to 3.7-fold), particularly in CD4+ lymphocytes, reaching proliferation levels comparable to control values. No effect of cAMP antagonist on T cell proliferation was seen in controls. In these CVI patients, cAMP antagonist also increased IL-2 production in anti-CD3-stimulated T cells. However, exogenously added IL-2 at concentrations comparable to the achieved increase in IL-2 levels after addition of cAMP antagonist had no effect on T cell proliferation. Furthermore, the stimulatory effects of exogenously added IL-2 at higher concentrations and cAMP antagonist on T cell proliferation were additive. Our findings indicate that increased PKAI activation may be an important molecular basis for the T cell defect in CVI and suggest that the cAMP/PKAI system may be a potential molecular target for immunomodulating therapy in these patients.

Adult↗
PubMed1999

Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.

OBJECTIVES: We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF). BACKGROUND: Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated. METHODS: Seventy-five patients (mean age 52 +/- 11 years) with CHF were randomized between low-(5 m g daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks). RESULTS: All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment. CONCLUSIONS: In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Administration of intravenous immunoglobulin (IVIG) in vivo--down-regulatory effects on the IL-1 system.

Modulation of the cytokine network may be of importance for the beneficial effects of therapy with IVIG seen in a wide range of immune-mediated disorders. In the present study we investigate the effect of IVIG administration in vivo on the IL-1 system in 12 patients with primary hypogammaglobulinaemia. Before IVIG infusion these patients had significantly elevated levels of IL-1alpha and IL-1beta both in plasma and in supernatants from peripheral blood mononuclear cells (PBMC) compared with healthy controls. After one bolus infusion with IVIG (0.4 g/kg) we found a significant change in the profile of the components of the IL-1 system: a marked increase in levels of IL-1 receptor antagonist (IL-1Ra) and neutralizing antibodies against IL-1alpha, a moderate decrease in levels of IL-1alpha, IL-1beta and soluble (s) IL-1 receptor type I and a significant increase in sIL-1 receptor type II levels. These changes were found both in plasma and in PBMC isolated after IVIG administration. Furthermore, pooled serum obtained after IVIG infusion suppressed lipopolysaccharide- and staphylococcal enterotoxin B-stimulated, but not phorbol myristate acetate-stimulated, release of IL-1alpha and IL-1beta from PBMC isolated from healthy controls. Finally, these changes in circulating levels of various IL-1 modulators after IVIG infusion appeared to cause a significantly impaired ability of IL-1 to stimulate PBMC for tumour necrosis factor-alpha release. Our findings suggest that IVIG administration may not only down-regulate the activity in the IL-1 system, but also hamper IL-1 stimulation of PBMC.

Adult↗
PubMed1999

IL-10 in HIV infection: increasing serum IL-10 levels with disease progression--down-regulatory effect of potent anti-retroviral therapy.

To examine the potential pathogenic role of IL-10 in HIV infection, we measured serum IL-10 levels in 51 HIV-infected patients and 23 healthy controls both on cross-sectional and longitudinal testing. All clinical groups (Centers for Disease Control (CDC) categories) of HIV-infected patients had significantly higher circulating IL-10 levels than controls, with the highest levels among the AIDS patients, particularly in patients with ongoing Mycobacterium avium complex (MAC) infection. Among 32 HIV-infected patients followed with longitudinal testing (median observation time 39 months), patients with disease progression had increasing IL-10 levels in serum, in contrast to non-progressing patients where levels were stable. While both IL-10 and tumour necrosis factor-alpha (TNF-alpha) increased in patients with disease progression, the IL-10/TNF-alpha ratio decreased in these patients, suggesting imbalance between these two cytokines. Finally, we found that highly active anti-retroviral therapy (HAART) induced a significant, gradual decrease in IL-10 levels but without normalization. These findings suggest a pathogenic role for IL-10 in HIV infection, and may suggest a possible role for immunomodulating therapy which down-regulates IL-10 activity in addition to concomitant potent anti-retroviral therapy in HIV-infected patients.

AIDS-Related Opportunistic Infections↗
PubMed1999

Tumor necrosis factor (TNF) system levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy: persistent TNF activation is associated with virologic and immunologic treatment failure.

Because persistent tumor necrosis factor (TNF)-alpha activation may play a pathogenic role in human immunodeficiency virus infection, TNF component levels were assessed over 78 weeks in plasma and peripheral blood mononuclear cells (PBMC) during highly active antiretroviral therapy (HAART) in 40 HIV-infected patients. HAART induced a significant decline in plasma levels of TNF-alpha and soluble TNF receptors and was associated with a fall in the abnormally increased unstimulated and a rise in the abnormally low Mycobacterium avium complex-purified-protein derivative-stimulated TNF-alpha released from PBMC. However, concentrations of these TNF components were not normalized. Patients with virologic and immunologic treatment failure after 52 weeks had higher levels of several TNF components than other patients early after initiation of therapy, also during periods with adequate virologic response. Although TNF components significantly decreased during HAART, these results support data indicating that full immunologic normalization is not achieved during such therapy. The persistent activation of the TNF system in a subgroup of persons may be involved in treatment failure.

Adolescent↗