228 HELLE ET AL. JCE & M • 2001
Vol. 86 • No. 1
tor- (TNF )] (20), and regulation of apoptosis (21). De- 106/L], and 13 were defined as nonprogressors (none had developed
creased levels of IGF-I may enhance lymphocyte apoptosis. AIDS, and all had CD4 T cell counts 150 106/L).
Previous studies have described a reduction in serum IGF-I Group 3. Another subgroup of 34 patients from group 1 was followed
and IGFBP-3 as well as increased IGFBP-3 protease activity during antiretroviral therapy. For these patients, the pretreatment sam-
in HIV-infected patients (9, 10). We hypothesize that alter- ple was the one used in the cross-sectional analysis. Twenty-five patients
ations in the IGF system during HIV infection, in particular received highly active antiretroviral therapy (HAART) with a protease
inhibitor in combination with 2 nucleoside analogs. For comparison 9
increased IGFBP-3 protease activity, are secondary events patients receiving only 2 nucleoside analogs (i.e. lamivudine and zidovu-
related to disease activity and thus are potentially reversible dine) were also selected for the study. They had immunological and
by specific therapy similar to our previous findings in breast virological responses similar to those of the patients receiving HAART.
cancer patients (22). To test this hypothesis, we evaluated Blood samples were obtained before treatment and later at 3-month
alteration in the IGF system in relation to virus load and
clinical and immunological parameters in different stages of
Blood sampling protocol
HIV infection in a cross-sectional study as an attempt to find
any mechanistic links among these parameters. We also ex- Venous blood was sampled into pyrogen-free blood collection tubes
amined the influence of antiretroviral therapy as well as the (Becton Dickinson and Co., San Jose, CA) with ethylenediamine tet-
raacetate as anticoagulant. Tubes were immediately immersed in melt-
natural course of the disease on the IGF system in subgroups ing ice and centrifuged (1000 g for 10 min) within 30 min. Plasma was
of the patients included. stored at 80 C, and samples were thawed only once.
Subjects and Methods Materials
Patients and controls Human recombinant IGF-I and IGF-II were purchased from GroPep
Group 1: cross-sectional analysis. Seventy-six HIV-seropositive patients Pty. Ltd. (Adelaide, Australia). IGF-I and IGF -II were iodinated using
were included in the study (59 men and 17 women; median age, 37 yr; the chloramine-T method. Labeled peptide was separated from nonin-
range, 17– 65 yr). Patients with ongoing acute or exacerbation of chronic corporated 125I by AcA 202 columns (BioSepra, Villeneuve, France) using
infection at the time of blood collection were not included. Based on their 1 40-cm columns.
clinical symptoms, the patients were classified according to the revised
criteria from Center for Disease Control and Prevention (CDC): 1) Assays
asymptomatic HIV-infected patients (n 26; CDC group A), 2) symp-
tomatic non-AIDS HIV-infected patients (n 13; CDC group B), and 3) Plasma levels of IGF-I (23) and IGF-II (17) were measured by RIA after
patients suffering from AIDS (n 37; CDC group C). Clinical and acid-acetone extraction (24). Intra- and interassay coefficients of varia-
immunological characteristics of the patients are shown in Table 1. tions were 3.5% and 6.2% for IGF-I and 5.5% and 12.9% for IGF-II,
Serum levels of alanine aminotransferase were less than 50 U/L, and respectively. Free IGF-I, IGFBP-3, and IGFBP-2 were measured by com-
serum creatinine levels were less than 100 mol/L in all patients. Fifty mercial kits (immunoradiometric assay/RIA) purchased from Diagnos-
patients received antiretroviral therapy with nucleoside analog(s), but tics Systems Laboratories, Inc. (Webster, TX) according to the manu-
none received HIV protease inhibitors, and none had initiated or facturer’s instructions.
changed therapy during the last 5 months before blood sampling. The IGFBP profile in the plasma was analyzed by Western ligand
Twenty healthy HIV-seronegative sex- and age-matched blood donors blotting (WLB) using a modified version (25) of the technique originally
were included as controls (Table 1). Oral informed consent for partic- developed by Hossenlopp (26). Radiolabeled IGFBPs were visualized by
ipating in the study was obtained from all patients and controls ac- autoradiography and quantified using a densitometric scanner (Phar-
cording to Norwegian regulations (6). macia Biotech, Uppsala, Sweden). The IGFBP pattern was compared
with the profile of a normal plasma pool (NP), and samples from each
Group 2. A subgroup of 26 patients (all included in group 1) were patient were analyzed in the same run for comparison. After WLB, the
observed over several years without antiretroviral therapy. These pa- membranes were immunoblotted using a polyclonal antiserum against
tients had blood samples taken at regular intervals for up to 6 yr. For each IGFBP-3 (Diagnostics Systems Laboratories, Inc., Webster, TX) at a final
of these patients, the last sample obtained was the one used in the dilution of 1:10,000. The membranes were then developed using en-
cross-sectional analysis (group 1). At the time of the first blood sampling hanced chemiluminescent reagents supplied by Amersham Pharmacia
all patients were in CDC group A or B, and all had CD4 T cell counts Biotech (Aylesbury, UK) according to the manufacturer’s instructions,
between 200 –500 106/L. At the end of the observation period, 13 of and the films were subjected to densitometric scanning. IGFBP-3 pro-
the patients were defined as progressors [all developed AIDS (8 had died tease activity was measured indirectly as IGFBP-3 fragmentation, de-
of HIV-related events) and all had a fall in CD4 T cell counts to 50 fined as the ratio of the major IGFBP-3 fragment (30 kDa) to total IGFBP-3
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)
Controls CDC group A CDC group B CDC group C
No. of patients 20 26 13 37
Median age (range) 38 (22– 60) 41 (22–57) 38 (23– 65) 39 (17– 62)
Males/females 15/5 18/8 11/2 32/5
CD4 lymphocytes ( 106/L) 608 (539 – 685) 257 (214 –311) 114 (59 –221) 15 (10 –25)
CD8 lymphocytes ( 106/L) 286 (238 –344) 772 (654 –912) 558 (403–772) 202 (138 –296)
HIV-1 RNA (103 copies/mL plasma) 24.9 (9.7– 64.4) 60.4 (14.4 –253.2) 364.0 (219.5– 604.4)
TNF (pmol/L) 0.4 (0.3– 0.5) 1.3 (1.1–1.5) 1.5 (1.0 –2.2) 4.6 (3.2– 6.7)
Glucose (mmol/L)a 5.0 (4.7–5.4) 5.0 (4.6 –5.4) 5.1 (4.7–5.5)
Triglycerides (mmol/L)a 1.6 (1.1–2.0) 1.9 (1.3–2.5) 3.6 (2.9 – 4.2)
Cholesterol (mmol/L)a 5.2 (4.8 – 6.2) 5.5 (5.0 – 6.0) 5.1 (4.7–5.6)
Values of laboratory parameters are given as mean (with 95% confidence intervals of the mean value).
Fasting blood samples.
THE IGF SYSTEM AND HIV INFECTION 229
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 , triglycerides, and cholesterol were measured as previous
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 dis-
tributed (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.
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. 1, 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.
Correlations between virological and immunological pa-
rameters and IGF parameters are shown in Table 2. Signif-
icant correlations were observed between the IGFBP-2 levels
and IGFBP-3 protease activity, on the one side, and virus
load, TNF 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 activ-
ity. Plasma levels of triglycerides correlated positively to
TNF (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).
FIG. 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%
Wasting in AIDS patients confidence intervals in controls (n 20), asymptomatic HIV-infected
Thirteen of 37 patients with AIDS had wasting. These 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;
patients had significantly lower levels of IGF-II (mean level,
n 37). A, By ANOVA: controls vs. CDC A vs. CDC B vs. CDC C, P
33.2 nmol/L; 95% confidence interval, 25.0 – 44.2; vs. mean, 0.060; controls vs. CDC (A B) vs. CDC C, P 0.028. By paired
55.8 nmol/L; 95% confidence interval, 48.7– 63.8; P 0.001) comparisons: controls vs. CDC (A B), P 0.035 CDC (A B) vs. CDC
and IGFBP-3 (P 0.04), but higher levels of IGFBP-2 (P C, P 0.33. B, By ANOVA: controls vs. CDC A vs. CDC B vs. CDC
0.01) compared with AIDS patients without wasting (Fig. 2). 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
Group 2: longitudinal analysis of IGF parameters in HIV- C, P 0.001; controls vs. CDC (A B) vs. CDC C, P 0.001. By paired
infected patients comparisons: controls vs. CDC (A B), P 0.986; CDC (A B) vs. CDC
C, P 0.001.
Of the 26 patients followed without any antiviral therapy
over several years (group B), disease remained stable in 13 nificant increase in the levels of IGFBP-2 and IGFBP-3 pro-
but progressed in the others (see Materials and Methods for tease activity and a decrease in intact IGFBP-3 measured by
definition). Although no changes were observed in the IGF Western ligand blot among patients with progressive disease
parameters in patients with stable disease, we found a sig- (Fig. 3).
230 HELLE ET AL. JCE & M • 2001
Vol. 86 • No. 1
TABLE 2. Group 1: correlations between immunological parameters and IGF parameters using Pearsons correlation test (rp)
CD4 T cells CD8 T cells Virus load TNF
(n 76) (n 76) (n 72) (n 72)
IGF-I 0.321a 0.157 0.024 0.219
IGF-II 0.090 0.079 0.031 0.245b
F-IGF-I 0.106 0.250b 0.067 0.059
IGFBP-2, RIA 0.633c 0.477c 0.482c 0.603c
IGFBP-3, RIA 0.153 0.136 0.119 0.220
IGFBP-3, protease 0.572c 0.467c 0.418c 0.525c
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 virolog-
ical disease. Finally, in patients with enhanced IGFBP-3 pro-
tease activity, potent antiretroviral therapy induced a
FIG. 2. Plasma levels (nanomoles per mL) of IGFBP-2 and IGFBP-3 marked decrease in this protease activity, significantly cor-
(with 95% confidence intervals of the mean) in AIDS patients with related with the virological and immunological effects of
wasting (n 13) compared with those in AIDS patients without such therapy.
wasting (n 24). In the cross-sectional part of this study we found a close
Group 3: the IGF system during antiretroviral therapy relationship between CD4 and CD8 cell counts as well as
A total of 34 patients were treated with 2 nucleoside an- viral load, on the one side, and IGFBP-3 protease activity and
alogs (n 9) or a combination of a protease inhibitor and 2 plasma IGFBP-2, on the other side. Interestingly, we also
nucleoside analogs (HAART; n 25). No difference between observed a strong positive correlation between IGFBP-2 lev-
the 2 treatment groups was found, suggesting that any effects els and IGFBP-3 protease activity. The observation that
on the IGF system during therapy were not related to the use plasma levels of IGFBP-2 levels, contrary to IGFBP-3 protease
of protease inhibitor. The data were therefore pooled for activity, were elevated in HIV-infected patients without
statistical analysis. We observed no significant change dur- AIDS suggests this binding protein to be the first IGF pa-
ing treatment in any of the IGF parameters, with the excep- rameter to change in this patient group. The mechanism
tion of IGFBP-3 measured by Western ligand blot (Table 3). behind this observation is not known. Increased IGFBP-2
However, there was a significant positive correlation be- levels have been found in other conditions, such as prostatic
tween alterations in virus load and IGFBP-3 protease activity cancer and lymphoma (28, 29), as well as in diabetes mellitus
(rp 0.441; P 0.04) and a negative correlation between (30). Interestingly, the expression of this binding protein has
alterations in IGFBP-3 protease activity (rp 0.497; P also been found in monocytes and T cells, with markedly
0.019) and CD8 T cell counts after 3 months of treatment. enhanced expression during activation of these cells (31).
Also, we observed a negative correlation between alterations HIV-infected patients are characterized by a sustained acti-
in the numbers of CD4 (rp 0.538; P 0.01) and CD8 vation of monocytes and T cells (1, 4). It is tempting to
(rp 0.447; P 0.037) T cells, on the one side, and IGFBP-2, hypothesize that the raised IGFBP-2 levels as well as other
on the other. All of these correlations, with exception of that alterations in the IGF system during HIV infection may be
between CD8 and IGFBP-2 (P 0.066), were still significant related to such a persistent immune activation in vivo. Our
when analyzing the HAART group alone. demonstration of a significant correlation between enhanced
Only five of the patients receiving antiretroviral therapy TNF levels and several disturbances in the IGF system
had an elevated ratio of fragmented to total IGFBP-3 ( 0.5) further support such an idea.
before commencing therapy. Each of these patients had a Advanced cancer (18, 29), poorly regulated diabetes mel-
decrease in IGFBP-3 protease activity during therapy. litus (32), critical illness (33), and major surgery (15, 16) have
all been found to produce elevated IGFBP-3 protease activity.
Discussion All of these conditions have in common an increased capil-
Our study confirms and extends some observations re- lary permeability in affected organs. IGFBP-3 protease ac-
corded in two previous smaller studies by Frost et al. in AIDS tivity is increased in extracellular fluid (34, 35), whereas little
THE IGF SYSTEM AND HIV INFECTION 231
F IG . 3. Alterations in IGF-I (A),
IGFBP-2 (B), IGFBP-3 protease activ-
ity (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 an-
tiviral treatment, comparing patients
with stable disease (open symbols) and
progressive disease (closed symbols).
For definition of disease progression,
see Materials and Methods.
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)
Measured levels (nmol/L) % of pretreatment levels
Before treatment (n 34) 3 months (n 22) 6 months (n 20) 9 months (n 9) 12 months (n 21) 18 months (n 13)
IGF-I 20.9 (18.6 –22.4) 106 (86 –113) 98 (86 –113) 121 (89 –164) 99 (90 –109) 103 (90 –120)
IGF-II 49.7 (43.4 –57.6) 105 (98 –113) 102 (95–109) 105 (94 –117) 112 (99 –127) 108 (89 –132)
F-IGF-I 0.20 (0.14 – 0.25) 107 (85–134) 102 (83–125) 101 (71–143) 100 (79 –128) 110 (70 –174)
IGFBP-2, RIA 28.9 (25.7–32.4) 95 (85–107) 100 (88 –115) 80 (62–103) 93 (84 –103) 88 (73–105)
IGFBP-2,a WLB 12.9 (9.8 –17.1) 94 (82–109) 107 (87–130) 71 (51–98) 90 (74 –109) 97 (63–151)
IGFBP-3, RIA 108.6 (94.5–122.7) 106 (96 –115) 109 (101–116) 120 (100 –141) 108 (98 –119) 105 (93–117)
IGFBP-3,a WLB 148 (115–190) 121 (106 –138) 121 (103–143) 141 (109 –182) 119 (100 –141) 152 (109 –210)
IGFBP-3,b protease 0.29 (0.23– 0.36) 83 (73–94) 97 (78 –120) 64 (45–91) 91 (73–114) 84 (53–134)
IGFBP-4,a WLB 2.8 (2.1–3.7) 86 (68 –110) 81 (65–101) 78 (52–116) 92 (68 –124) 99 (66 –146)
Ratio of fragmented to total IGFBP-3.
intravascular IGFBP-3 protease activity occurs in healthy HAART. This may be due to several factors. The number of
subjects (36). We recently demonstrated endothelial dysfunc- patients with advanced disease in this part of the study was
tion during HIV infection (37), possibly secondary to en- limited. We observed a pretreatment mean value of ratio of
hanced activation of inflammatory cytokines (38). Notably, fragmented to total IGFBP-3 of 0.29, which does not differ
inflammatory cytokines such as IL-1 and TNF have also much from what has been recorded in normal subjects (36).
been found to enhance IGFBP-3 protease activity (39), and However, all five patients with a ratio of fragmented to total
similar mechanisms may well be operating in HIV-infected IGFBP-3 greater than 0.5 had a decrease in this ratio with a
individuals. corresponding increase in IGFBP-3 measured with Western
We found no significant impact on the IGF system during ligand blot after 3– 6 months of treatment. Any significant
232 HELLE ET AL. JCE & M • 2001
Vol. 86 • No. 1
effects may thus be masked by minor alterations in patients 6. Aukrust P, Haug C, Ueland T, et al. 1999 Decreased bone formation and
enhanced resorptive markers in human immunodeficiency virus infection:
with near-normal IGFBP-3 protease activity. The small num- indication of normalization of the bone-remodeling process during highly
ber of observations does not permit any firm conclusion active antiretroviral therapy. J Clin Endocrinol Metab. 84:145–150.
regarding this issue, but the decrease in inflammatory cy- 7. Danoff A. 1996 Endocrinological complications of HIV infection. Med Clin
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9. Frost RA, Nachman SA, Lang CH, Gelato MC. 1996 Proteolysis of insulin-like
ated with a syndrome of lipodystropy, hyperlipidemia, and growth factor-binding protein-3 in human immunodeficiency virus-positive
insulin resistance (41). Our data do not suggest alterations in children who fail to thrive. J Clin Endocrinol Metab. 81:2957–2962.
the IGF system to be involved in its development, but we 10. Frost RA, Fuhrer J, Steigbigel R, Mariuz P, Lang CH, Gelato MC. 1996
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13. Lassarre C, Binoux M. 1994 Insulin-like growth factor binding protein-3 is
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Both AIDS and cancer patients develop wasting in the ad- growth factor binding proteins in maternal serum throughout gestation and
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However, this low molecular mass complex has a higher 20. Renier G, Clement I, Desfaits A-C, Lambert A. 1996 Direct stimulatory effect
of insulin-like growth factor-I on monocyte and macrophage tumor necrosis
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