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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 227-233
Copyright © 2001 by The Endocrine Society

Original Studies

The Insulin-Like Growth Factor System in Human Immunodeficiency Virus Infection: Relations to Immunological Parameters, Disease Progression, and Antiretroviral Therapy1

S. I. Helle, T. Ueland, D. Ekse, S. S. Frøland, J. M. P. Holly, P. E. Lønning and P. Aukrust

Department of Oncology, Haukeland University Hospital (S.I.H., D.E., P.E.L.), N-5021 Bergen, Norway; Sections of Clinical Immunology and Infectious Diseases (P.A., S.S.F.), Endocrinology (T.U.), Medical Department, and Research Institute for Internal Medicine (P.A., S.S.F.), National Hospital-Rikshospitalet, Oslo, Norway; and Department of Surgery (J.M.P.H.), Bristol Royal Infirmary, Bristol, United Kingdom

Address all correspondence and requests for reprints to: Prof. Per E. Lønning, Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Endocrine dysfunctions have previously been reported in human immunodeficiency virus (HIV) infection. In this study we evaluated the relation of immunological parameters, virus load, clinical stage, and wasting to several parameters of the insulin-like growth factor (IGF) system in 76 patients with HIV infection, of whom 37 had developed acquired immune deficiency syndrome (AIDS). A subgroup of 26 untreated patients was followed during longitudinal testing, while the effects of antiretroviral therapy were evaluated in 34 patients (nucleoside analogs in 9, nucleoside analogs in combination with protease inhibitors in 25). Twenty healthy sex- and age-matched controls were analyzed for comparison.

IGF-II was decreased (P = 0.03) and IGF-binding protein-2 (IGFBP-2) and IGFBP-3 protease activity were increased (P < 0.001) in AIDS patients compared with other HIV-infected individuals and controls. Plasma levels of IGFBP-2 and IGFBP-3 protease activity correlated positively to virus load (P < 0.001) and tumor necrosis factor-{alpha} (P < 0.025) and negatively to CD4+ and CD8+ cell counts (P < 0.001). AIDS patients with wasting (n = 13) had lower IGF-II levels (P = 0.001) and higher IGFBP-2 levels (P = 0.001) than other AIDS patients. Although no significant change in any of the IGF-parameters was observed in patients during antiretroviral therapy, patients with elevated IGFBP-3 protease activity before therapy (5 of 34) all had a decrease during treatment. During longitudinal testing in patients followed without antiretroviral therapy, disease progression was associated with increases in IGFBP-3 protease activity and IGFBP-2 levels. Our results reveal several alterations in the IGF system during HIV infection with decreased IGF-II levels, increased concentration of IGFBP-2, and an increased IGFBP-3 protease activity in advanced disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INFECTION WITH human immunodeficiency virus (HIV) causes progressive immunodeficiency, predisposing to a number of secondary diseases. These include a variety of opportunistic infections, malnourishment, and diarrhea (1) as well as an elevated risk for different malignancies, in particular lymphoma (2) and Kaposi’s sarcoma (3). Several factors may be involved in the pathogenesis of these conditions including numerical and functional disturbances of CD4+ T cells (4), increased production of proinflammatory cytokines (5), and altered function of monocytes/macrophages (4).

Although these immunological factors may be responsible for the bulk of the pathological changes observed, HIV infection is also associated with various endocrine abnormalities, such as altered bone homeostasis, hypogonadism, adrenal and thyroid dysfunction as well as hyperinsulinemia (6, 7, 8). There are also some pilot studies indicating disturbances in the insulin-like growth factor (IGF) system in acquired immune deficiency syndrome (AIDS) patients with wasting and in children who fail to thrive (9, 10).

IGF-I plays a pivotal role in many physiological processes as the mediator of the effects of GH (11). Although it executes its function as a ligand to the IGF-I receptor, its action is modified by six IGF-binding proteins (IGFBPs), which have been shown to enhance or inhibit its biological activity depending on experimental conditions (12). The major IGFBP in the circulation is IGFBP-3. Together with another protein, the acid-labile subunit, IGFBP-3 forms a 150-kDa ternary complex with IGF-I or -II that binds more than 90% of circulating IGF-I in normal subjects. IGFBP-3 is subject to proteolysis (13), resulting in fragments still able to complex with acid-labile subunit and IGFs, but with a significantly reduced affinity. Protease activity for IGFBP-3 has been found to be elevated in pregnancy (14), but also after major surgery (15, 16) and in patients suffering from septicemia (17) or cancer (18, 19).

Several previous findings indicate a role for the IGF system in the pathogenesis of HIV infection. In addition to potent anabolic effects, recent studies suggest that the IGF system may be involved in various immunological and inflammatory processes, such as monocyte chemotaxis and activation, induction of inflammatory cytokines [e.g. tumor necrosis factor-{alpha} (TNF{alpha})] (20), and regulation of apoptosis (21). Decreased levels of IGF-I may enhance lymphocyte apoptosis. Previous studies have described a reduction in serum IGF-I and IGFBP-3 as well as increased IGFBP-3 protease activity in HIV-infected patients (9, 10). We hypothesize that alterations in the IGF system during HIV infection, in particular increased IGFBP-3 protease activity, are secondary events related to disease activity and thus are potentially reversible by specific therapy similar to our previous findings in breast cancer patients (22). To test this hypothesis, we evaluated alteration in the IGF system in relation to virus load and clinical and immunological parameters in different stages of HIV infection in a cross-sectional study as an attempt to find any mechanistic links among these parameters. We also examined the influence of antiretroviral therapy as well as the natural course of the disease on the IGF system in subgroups of the patients included.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and controls

Group 1: cross-sectional analysis. Seventy-six HIV-seropositive patients were included in the study (59 men and 17 women; median age, 37 yr; range, 17–65 yr). Patients with ongoing acute or exacerbation of chronic infection at the time of blood collection were not included. Based on their clinical symptoms, the patients were classified according to the revised criteria from Center for Disease Control and Prevention (CDC): 1) asymptomatic HIV-infected patients (n = 26; CDC group A), 2) symptomatic non-AIDS HIV-infected patients (n = 13; CDC group B), and 3) patients suffering from AIDS (n = 37; CDC group C). Clinical and immunological characteristics of the patients are shown in Table 1Go. Serum levels of alanine aminotransferase were less than 50 U/L, and serum creatinine levels were less than 100 µmol/L in all patients. Fifty patients received antiretroviral therapy with nucleoside analog(s), but none received HIV protease inhibitors, and none had initiated or changed therapy during the last 5 months before blood sampling. Twenty healthy HIV-seronegative sex- and age-matched blood donors were included as controls (Table 1Go). Oral informed consent for participating in the study was obtained from all patients and controls according to Norwegian regulations (6).


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  		Table 1. Clinical characteristics of the 76 patients and 20 controls included in the study): CDC group A (asymptomatic HIV infected patients), CDC group B (symptomatic non-AIDS HIV-infected patients), and CDC group C (patients suffering from AIDS)

 
Group 2. A subgroup of 26 patients (all included in group 1) were observed over several years without antiretroviral therapy. These patients had blood samples taken at regular intervals for up to 6 yr. For each of these patients, the last sample obtained was the one used in the cross-sectional analysis (group 1). At the time of the first blood sampling all patients were in CDC group A or B, and all had CD4+ T cell counts between 200–500 x 106/L. At the end of the observation period, 13 of the patients were defined as progressors [all developed AIDS (8 had died of HIV-related events) and all had a fall in CD4+ T cell counts to <50 x 106/L], and 13 were defined as nonprogressors (none had developed AIDS, and all had CD4+ T cell counts >150 x 106/L).

Group 3. Another subgroup of 34 patients from group 1 was followed during antiretroviral therapy. For these patients, the pretreatment sample was the one used in the cross-sectional analysis. Twenty-five patients received highly active antiretroviral therapy (HAART) with a protease inhibitor in combination with 2 nucleoside analogs. For comparison 9 patients receiving only 2 nucleoside analogs (i.e. lamivudine and zidovudine) were also selected for the study. They had immunological and virological responses similar to those of the patients receiving HAART. Blood samples were obtained before treatment and later at 3-month intervals.

Blood sampling protocol

Venous blood was sampled into pyrogen-free blood collection tubes (Becton Dickinson and Co., San Jose, CA) with ethylenediamine tetraacetate as anticoagulant. Tubes were immediately immersed in melting ice and centrifuged (1000 x g for 10 min) within 30 min. Plasma was stored at -80 C, and samples were thawed only once.

Materials

Human recombinant IGF-I and IGF-II were purchased from GroPep Pty. Ltd. (Adelaide, Australia). IGF-I and IGF -II were iodinated using the chloramine-T method. Labeled peptide was separated from nonincorporated 125I by AcA 202 columns (BioSepra, Villeneuve, France) using 1 x 40-cm columns.

Assays

Plasma levels of IGF-I (23) and IGF-II (17) were measured by RIA after acid-acetone extraction (24). Intra- and interassay coefficients of variations were 3.5% and 6.2% for IGF-I and 5.5% and 12.9% for IGF-II, respectively. Free IGF-I, IGFBP-3, and IGFBP-2 were measured by commercial kits (immunoradiometric assay/RIA) purchased from Diagnostics Systems Laboratories, Inc. (Webster, TX) according to the manufacturer’s instructions.

The IGFBP profile in the plasma was analyzed by Western ligand blotting (WLB) using a modified version (25) of the technique originally developed by Hossenlopp (26). Radiolabeled IGFBPs were visualized by autoradiography and quantified using a densitometric scanner (Pharmacia Biotech, Uppsala, Sweden). The IGFBP pattern was compared with the profile of a normal plasma pool (NP), and samples from each patient were analyzed in the same run for comparison. After WLB, the membranes were immunoblotted using a polyclonal antiserum against IGFBP-3 (Diagnostics Systems Laboratories, Inc., Webster, TX) at a final dilution of 1:10,000. The membranes were then developed using enhanced chemiluminescent reagents supplied by Amersham Pharmacia Biotech (Aylesbury, UK) according to the manufacturer’s instructions, and the films were subjected to densitometric scanning. IGFBP-3 protease activity was measured indirectly as IGFBP-3 fragmentation, defined as the ratio of the major IGFBP-3 fragment (30 kDa) to total IGFBP-3 evaluated by densitometric scanning on immunoblots. A ratio above 0.5 was arbitrarily considered elevated IGFBP-3 protease activity.

Plasma HIV ribonucleic acid levels were measured by quantitative reverse PCR (Amplicor HIV Monitor, Roche, Branchburg, NJ; detection limit, 200 copies/mL). The numbers of CD4+ and CD8+ T cells in peripheral blood were determined by immunomagnetic quantification. Plasma TNF{alpha}, triglycerides, and cholesterol were measured as previous described (27).

Statistical analysis

In a previous study we found plasma levels of IGF-I and -II to be well fitted to a log normal distribution, whereas IGFBP-3 was normally distributed (22). Thus, parameters are given as their geometric mean value with 95% confidence intervals of the mean, with the exception of IGFBP-3 RIA for which arithmetic mean values are given. The measured parameters obtained in different patient groups were compared using ANOVA or Student’s t test. Correlations between different parameters were tested using the SYSTAT program (Systat, Evanston, IL) on a Macintosh computer. Univariate analyses were performed using the Pearson correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Group 1: the IGF system in relation to clinical, immunological, and virological parameters in HIV-infected patients: cross-sectional analysis

Comparing the control group (n = 20), CDC group A (n = 26), CDC group B (n = 13), and patients with AIDS (CDC group C; n = 37) revealed significant differences among the groups in plasma levels of IGF-II and IGFBP-2 as well as IGFBP-3 protease activity (Fig. 1Go, see P values in footnote). In summary, IGF-II levels were higher in normal subjects, whereas IGFBP-2 and IGFBP-3 protease activities were increased in AIDS patients compared with the other groups.



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  		Figure 1. Mean values of IGF-II (A), IGFBP-2 (RIA; B), and IGFBP-3 protease activity (C; given as fragmented to total IGFBP-3) with 95% confidence intervals in controls (n = 20), asymptomatic HIV-infected patients in (CDC group A; n = 26), symptomatic non-AIDS patients (CDC group B; n = 13), as well as patients with AIDS (CDC group C; n = 37). A, By ANOVA: controls vs. CDC A vs. CDC B vs. CDC C, P = 0.060; controls vs. CDC (A+B) vs. CDC C, P = 0.028. By paired comparisons: controls vs. CDC (A+B), P = 0.035 CDC (A+B) vs. CDC C, P = 0.33. B, By ANOVA: controls vs. CDC A vs. CDC B vs. CDC C, P < 0.001; controls vs. CDC (A+B) vs. CDC C, P < 0.001. By paired comparisons: controls vs. CDC (A+B), P <0.001; CDC (A+B) vs. CDC C, P < 0.001. C, By ANOVA: controls vs. CDC A vs. CDC B vs. CDC C, P < 0.001; controls vs. CDC (A+B) vs. CDC C, P < 0.001. By paired comparisons: controls vs. CDC (A+B), P = 0.986; CDC (A+B) vs. CDC C, P < 0.001.

 
Correlations between virological and immunological parameters and IGF parameters are shown in Table 2Go. Significant correlations were observed between the IGFBP-2 levels and IGFBP-3 protease activity, on the one side, and virus load, TNF{alpha} levels (positive correlation), and CD4+ and CD8+ T cell counts (negative correlations) on the other side. We also observed a strong positive correlation (rp = 0.500; P < 0.001) between IGFBP-2 concentration and IGFBP-3 protease activity. Plasma levels of triglycerides correlated positively to TNF{alpha} (rp = 0.868; P < 0.001), IGFBP-2 (rp = 0.542; P < 0.001), and IGFBP-3 protease activity (rp = 0.482; P < 0.001).


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  		Table 2. Group 1: correlations between immunological parameters and IGF parameters using Pearsons correlation test (rp)

 
Wasting in AIDS patients

Thirteen of 37 patients with AIDS had wasting. These patients had significantly lower levels of IGF-II (mean level, 33.2 nmol/L; 95% confidence interval, 25.0–44.2; vs. mean, 55.8 nmol/L; 95% confidence interval, 48.7–63.8; P < 0.001) and IGFBP-3 (P = 0.04), but higher levels of IGFBP-2 (P < 0.01) compared with AIDS patients without wasting (Fig. 2Go).



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  		Figure 2. Plasma levels (nanomoles per mL) of IGFBP-2 and IGFBP-3 (with 95% confidence intervals of the mean) in AIDS patients with wasting (n = 13) compared with those in AIDS patients without wasting (n = 24).

 
Group 2: longitudinal analysis of IGF parameters in HIV-infected patients

Of the 26 patients followed without any antiviral therapy over several years (group B), disease remained stable in 13 but progressed in the others (see Materials and Methods for definition). Although no changes were observed in the IGF parameters in patients with stable disease, we found a significant increase in the levels of IGFBP-2 and IGFBP-3 protease activity and a decrease in intact IGFBP-3 measured by Western ligand blot among patients with progressive disease (Fig. 3Go).



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  		Figure 3. Alterations in IGF-I (A), IGFBP-2 (B), IGFBP-3 protease activity (C), and IGFBP-3 (D; by Western ligand blot) shown as the percent change from baseline levels with 95% confidence intervals in HIV-infected patients observed without specific antiviral treatment, comparing patients with stable disease (open symbols) and progressive disease (closed symbols). For definition of disease progression, see Materials and Methods.

 
Group 3: the IGF system during antiretroviral therapy

A total of 34 patients were treated with 2 nucleoside analogs (n = 9) or a combination of a protease inhibitor and 2 nucleoside analogs (HAART; n = 25). No difference between the 2 treatment groups was found, suggesting that any effects on the IGF system during therapy were not related to the use of protease inhibitor. The data were therefore pooled for statistical analysis. We observed no significant change during treatment in any of the IGF parameters, with the exception of IGFBP-3 measured by Western ligand blot (Table 3Go). However, there was a significant positive correlation between alterations in virus load and IGFBP-3 protease activity (rp = 0.441; P = 0.04) and a negative correlation between alterations in IGFBP-3 protease activity (rp = -0.497; P = 0.019) and CD8+ T cell counts after 3 months of treatment. Also, we observed a negative correlation between alterations in the numbers of CD4+ (rp = -0.538; P = 0.01) and CD8+ (rp = -0.447; P = 0.037) T cells, on the one side, and IGFBP-2, on the other. All of these correlations, with exception of that between CD8+ and IGFBP-2 (P = 0.066), were still significant when analyzing the HAART group alone.


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  		Table 3. Values of IGF-I, F-IGF-I, IGF-II, IGFBP-2, and IGFBP-3 measured by RIA/IRMA and of IGFBP-2, -3, and -4 by Western ligand blot (WLB) before and percentage of pretreatment levels/percent change at various intervals in patients with HIV infection during treatment with protease inhibitors and nucleotide analogs (see Materials and Methods)

 
Only five of the patients receiving antiretroviral therapy had an elevated ratio of fragmented to total IGFBP-3 (>0.5) before commencing therapy. Each of these patients had a decrease in IGFBP-3 protease activity during therapy.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study confirms and extends some observations recorded in two previous smaller studies by Frost et al. in AIDS patients with wasting and in HIV-infected children (9, 10). First, we found that the most marked alteration in the IGF system during HIV infection was a decrease in IGF-II levels accompanied by raised IGFBP-2 levels and increased IGFBP-3 protease activity, as demonstrated in both cross-sectional and longitudinal testing. Second, some of these disturbances in the IGF system (i.e. decreased IGF-II and raised IGFBP-2 levels) were not restricted to AIDS patients, but were also found in HIV-infected patients who had not developed AIDS. Third, the alterations in the IGF system, particularly raised IGFBP-2 levels and IGFBP-3 protease activity, were correlated to advanced clinical, immunological, and virological disease. Finally, in patients with enhanced IGFBP-3 protease activity, potent antiretroviral therapy induced a marked decrease in this protease activity, significantly correlated with the virological and immunological effects of such therapy.

In the cross-sectional part of this study we found a close relationship between CD4+ and CD8+ cell counts as well as viral load, on the one side, and IGFBP-3 protease activity and plasma IGFBP-2, on the other side. Interestingly, we also observed a strong positive correlation between IGFBP-2 levels and IGFBP-3 protease activity. The observation that plasma levels of IGFBP-2 levels, contrary to IGFBP-3 protease activity, were elevated in HIV-infected patients without AIDS suggests this binding protein to be the first IGF parameter to change in this patient group. The mechanism behind this observation is not known. Increased IGFBP-2 levels have been found in other conditions, such as prostatic cancer and lymphoma (28, 29), as well as in diabetes mellitus (30). Interestingly, the expression of this binding protein has also been found in monocytes and T cells, with markedly enhanced expression during activation of these cells (31). HIV-infected patients are characterized by a sustained activation of monocytes and T cells (1, 4). It is tempting to hypothesize that the raised IGFBP-2 levels as well as other alterations in the IGF system during HIV infection may be related to such a persistent immune activation in vivo. Our demonstration of a significant correlation between enhanced TNF{alpha} levels and several disturbances in the IGF system further support such an idea.

Advanced cancer (18, 29), poorly regulated diabetes mellitus (32), critical illness (33), and major surgery (15, 16) have all been found to produce elevated IGFBP-3 protease activity. All of these conditions have in common an increased capillary permeability in affected organs. IGFBP-3 protease activity is increased in extracellular fluid (34, 35), whereas little intravascular IGFBP-3 protease activity occurs in healthy subjects (36). We recently demonstrated endothelial dysfunction during HIV infection (37), possibly secondary to enhanced activation of inflammatory cytokines (38). Notably, inflammatory cytokines such as IL-1 and TNF{alpha} have also been found to enhance IGFBP-3 protease activity (39), and similar mechanisms may well be operating in HIV-infected individuals.

We found no significant impact on the IGF system during HAART. This may be due to several factors. The number of patients with advanced disease in this part of the study was limited. We observed a pretreatment mean value of ratio of fragmented to total IGFBP-3 of 0.29, which does not differ much from what has been recorded in normal subjects (36). However, all five patients with a ratio of fragmented to total IGFBP-3 greater than 0.5 had a decrease in this ratio with a corresponding increase in IGFBP-3 measured with Western ligand blot after 3–6 months of treatment. Any significant effects may thus be masked by minor alterations in patients with near-normal IGFBP-3 protease activity. The small number of observations does not permit any firm conclusion regarding this issue, but the decrease in inflammatory cytokines, including TNF {alpha} (40), during HAART may be one possible effector mechanism.

Treatment with protease inhibitors is frequently associated with a syndrome of lipodystropy, hyperlipidemia, and insulin resistance (41). Our data do not suggest alterations in the IGF system to be involved in its development, but we have not been able to fully evaluate this issue due to lack of data on insulin and lipid parameters during treatment.

Alterations in IGF parameters in patients with clinical disease progression in the longitudinal part of the study resemble what has been observed in cancer patients with progressive disease (22). This may indicate a common final pathway behind the increase in IGFBP-3 protease activity. Both AIDS and cancer patients develop wasting in the advanced setting. Only plasma levels of IGF-II (decreased) and IGFBP-2 (increased) were different between AIDS patients with and without wasting. No clear relation to IGFBP-3 protease activity, IGF-I, and free IGF-I could be found. However, the small number of patients in this part of the analysis, comparing rather similar groups regarding disease severity, does not refute the importance of the IGF system in development of wasting.

Although it is speculative to draw any firm conclusions when evaluating such a complicated system, our data support a reduced amount of bioavailable IGFs to the normal tissue in advanced HIV infection due primarily to decreased levels of IGF-II. Furthermore, a decreased amount of intact IGFBP-3 depletes the normal plasma depot of IGFs in the 150-kDa complex, causing redistribution of these growth factors to IGFBP-2, which may act as an alternative carrier. However, this low molecular mass complex has a higher turnover rate, and most data suggest IGFBP-2 to have predominantly inhibitory effects on IGF actions (42). Thus, one might hypothesize that the combination of low IGF-II and high IGFBP-2 found in advanced HIV infection may contribute to the enhanced degree of lymphocyte apoptosis in these patients, particularly when accompanied by high levels of proapoptotic mediators such as TNF{alpha}. These abnormalities may, in turn, contribute to the pathogenesis of immune dysfunction in these patients, possibly representing a vicious circle in HIV infection.


   Acknowledgments
 
We thank Beryl Leirvaag and Bodil Lunden for excellent technical assistance.


   Footnotes
 
1 This work was supported by the Norwegian Cancer Society. Back

Received May 2, 2000.

Revised September 12, 2000.

Accepted September 19, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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