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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2084-2092
By
From The Institute of Cancer Research and Molecular Biology,
Norwegian University of Science and Technology, University Medical
Center, Trondheim, Norway; and the Section of Clinical Immunology and
Infectious Diseases, Medical Department A and Research Institute for
Internal Medicine, University of Oslo, The National Hospital, Oslo,
Norway.
Soluble (s) CD14, a marker for monocyte/macrophage activation and a
mediator of bacterial lipopolysaccharide (LPS) action, was elevated in
serum from human immunodeficiency virus type 1 (HIV- 1)-infected
individuals (n = 92) compared with seronegative controls. The highest
levels were found in patients with advanced clinical and immunological
disease. Patients with ongoing clinical events had significantly higher
sCD14 levels than symptomatic HIV-1-infected individuals without
clinical events, with especially elevated levels in patients infected
with Mycobacterium avium complex (MAC). On longitudinal testing
of patients (n = 26) with less than 100 × 106
CD4 lymphocytes/L at baseline, we found that increasing sCD14 serum
concentrations per time unit were associated with death, whereas no
differences in CD4 cell number decrease were found between survivors
and nonsurvivors. In vitro studies showed that HIV-1 glycoprotein 120 and purified protein derivative (PPD) from M avium (MAC-PPD)
stimulated normal monocytes to release sCD14. Furthermore, MAC-PPD
induced tumor necrosis factor (TNF) release from monocytes
through interactions with CD14 and, importantly, the addition of sCD14
enhanced this MAC-PPD stimulatory effect. Our findings suggest that the
CD14 molecule may be involved in the immunopathogenesis of HIV-1
infection, and it is conceivable that serial determination of sCD14 may
give useful predictive information concerning disease progression and
survival in HIV-1-infected patients.
© 1998 by The American Society of Hematology.
AN IMPORTANT QUESTION regarding the
pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection
is the altered activation status and reaction pattern for different
cell populations of the immune system. Monocytes and macrophages are
reservoirs for HIV-1, and these cells produce altered levels of
cytokines1 and have impaired ability to kill microorganisms
such as Mycobacterium avium.2 CD14 (reviewed by
Ziegler Heitbrock and Ulevitch3) is a glycoprotein
expressed mainly on the surface of monocytes/macrophages and, to a
lesser extent, on neutrophils.3,4 Membrane (m) CD14 is a
receptor for bacterial lipopolysaccharide (LPS), but soluble (s) CD14
may also bind LPS directly and enhance LPS responses in cells that lack
mCD14.5,6 However, both enhancing7,8 and
inhibitory9;10 effects are observed when sCD14 is added
together with LPS to monocyte cell cultures depending on type and
concentration of sCD14. Recently, a cell surface structure distributed
on many cell types was postulated as a receptor for sCD14/LPS
complexes, and this structure may also be involved in interactions with
mCD14.11 CD14 has been implicated in the activation of
cells by molecules other than LPS, eg, streptococcal rhamnose glucose
polymers,12 cell wall components from Staphylococcus
aureus,13-15 lipoarabinomannan (LAM) from
Mycobacterium,16,17 and mannuronan isolated
from seaweed or Pseudomonas aeruginosa.18,19 It has
also been identified as a phospholipid transfer molecule20;
additionally, a role of CD14 in monocyte interleukin-2 (IL-2) signaling
has been reported.21
sCD14, which exists in two different forms with molecular weights of 48 and 54 kD, respectively, is either shedded from the cell surface or
released from intracellular pools.22 Increased release of
sCD14 from monocytes is observed after stimulation with various
agents,22-25 and sCD14 may therefore be a marker for activation of monocytes/macrophages. In normal serum, sCD14 is present
in relatively high concentrations (>1 µg/mL) and elevated serum
levels have been reported in disorders such as trauma,26 sepsis,27,28 and rheumatoid arthritis.29;30
There is also one report demonstrating elevated levels in HIV-1 infection in a cross-sectional study.31 Earlier, we and
others have described increased concentrations of activation
parameters, such as tumor necrosis factor Patients
Enzyme-Linked Immunosorbent Assay (ELISA) for sCD14
Analysis of Blood CD4 Lymphocytes The number of CD4 lymphocytes in blood were determined by immunomagnetic quantification as described.37Measurement of HIV-1 RNA Copies in Plasma HIV-1 RNA copy numbers in plasma were measured by quantitative reverse transcriptase polymerase chain reaction (PCR; Amplicor HIV monitor; Roche Diagnostic Systems, Branchburg, NJ). The detection limit of the assay was 200 copies/mL.Stimulation of Cells Cells. Monolayer cultures of adherent human monocytes from healthy blood donors were prepared using gradient centrifugation of buffy coat (The Blood Bank, University Hospital of Trondheim, Trondheim, Norway) on Lymphoprep (Nycomed, Oslo, Norway). The peripheral blood mononuclear cell fraction (2 × 106 cells/well) was incubated in 24-well cell culture plates (Costar, Cambridge, MA) for 1.5 hours in culture medium (see below) containing 40 µg/mL gentamicin and 1% glutamin. Nonadherent cells were removed by washing three times with Hank's Balanced Salt Solution (GIBCO, Paisley, UK). This method gave typically more than 92% CD14+ cells as determined by flow cytometry (results not shown). Cell isolations yielded 4 to 8 × 105 monocytes/well. Stimulations with HIV-1 gp120. Recombinant HIV-1 IIIB gp120 derived from baculovirus-infected insect cells (obtained through MRC AIDS Reagent Project, Potters Bar, UK) was added to monocytes in RPMI 1640 medium (GIBCO) containing 10% fetal calf serum (FCS; GIBCO) for 72 hours. For immunodepletion of gp120, 100 µL goat antimouse sepharose gel (Zymed, San Francisco, CA) was incubated in the presence or absence (for control) of 50 µg gp120 MoAb (obtained through MRC AIDS Reagent Project, UK) with end-over-end rotation for 4 hours. The gel was washed, and nonspecific binding was blocked with 0.1% BSA in PBS and incubated with a 10 µg/mL gp120 solution for 14 hours with end-over-end rotation. The gp120 content in solution after depletion was analyzed in an ELISA with recombinant sCD4 (Intracel, London, UK) coating, sample incubation, and detection with polyclonal rabbit anti-gp120 antibodies (IgG fraction; Intracel) and peroxidase-conjugated goat anti-rabbit antibodies/OPD substrate (Dako). The ELISA demonstrated removal of more than 99.6% of gp120 in the immunodepletion. Equal amounts of liquid from the gp120-immunodepleted solution and control (equivalent to 0.4 and 0.2 µg/mL gp120 according to the ELISA) were then added to monocytes and incubated for 72 hours. By use of Limulus amoebocyte lysate assay (Chromogenix, Mölndal, Sweden), endotoxin contamination was measured to 8 pg/µg for gp120. Cell supernatants were analyzed in the sCD14 ELISA as described above. Stimulations with purified protein derivative from M avium (MAC-PPD) and LPS. Adherent monocytes were stimulated with PPD from M avium (MAC-PPD) or LPS from Escherichia coli O26:B6 (catalogue no. L8274; Sigma) in AIM V serum-free medium (GIBCO). MAC-PPD (generously provided by Reidar Bjørlo, The National Veterinary Institute, Oslo, Norway) was produced from M avium strain D4ER (provided by Central Veterinary Laboratory, Weybridge, UK) after main principles, as described.38 Briefly, the bacteria were grown on Sutong-medium, and PPD was prepared from filtrate after precipitation with 40% trichloroacetic acid and subsequent washings with 2% trichloroacetic acid, aceton, and ether. For study of sCD14-release, cells were stimulated for 72 hours. In separate experiments, monocytes were stimulated for 8 hours to investigate the release of TNF. To modulate the stimulatory response mediated by MAC-PPD, the following reagents were used: LPS-neutralizing MoAb 3C10 against CD14, control MoAb 6H8 against a widely distributed myeloid cell surface protein (B. Naume and T. Espevik, unpublished results), and recombinant sCD14 (Amgen). Supernatants were analyzed for bioactive TNF in the WEHI 164 clone 13 bioassay, as described.39 The endotoxin content of MAC-PPD was 0.7 pg/µg as measured by the Limulus assay (Chromogenix). Statistics For statistical analysis, the Wilcoxon rank-sum (Mann-Whitney U) test was used for comparing two groups. The Kruskal-Wallis test was used for comparing more than two groups, and correlation analysis was performed using Spearman's rank correlation coefficients. Results are given as medians with the corresponding 25 to 75 percentiles, unless otherwise specified. For calculations of change in parameters over time, linear regression was used. The influence of different parameters on survival was studied using Kaplan-Meyer analysis and the log rank test. P values less than .05 were considered significant. Data were analyzed with the SPSS for Windows statistical software (SPSS Inc, Chicago, IL).
Increasing Levels of sCD14 Throughout HIV-1 Infection We found a significant increase of serum sCD14 levels in all clinical stages of HIV-1 infection compared with controls (Fig 1). In fact, the increase in sCD14 was more pronounced in patients with AIDS (CDC group C) than in individuals from the asymptomatic group (CDC group A) or the symptomatic non-AIDS group (CDC group B). The differences between sCD14 levels in AIDS (CDC group C) and non-AIDS (CDC groups A and B, respectively) patients were highly significant.
Correlation to Other Immunological Parameters
Correlation of sCD14 Concentrations to Viral Load To correlate amounts of sCD14 in serum to the viral load in patients, we measured HIV-1 RNA copy numbers by PCR in plasma samples from 49 patients in the study (median, 50,954 copies/mL; 25 to 75 percentile, 6,790 to 311,751 copies/mL). Interestingly, we found a highly significant correlation (r = .69, P < .001) between sCD14 and the amount of plasma HIV-1 RNA, as shown in Fig 3. In addition to the relationship between sCD14 and different immunological parameters, this further demonstrates the close correlation between disease activity and serum sCD14 concentrations.
Longitudinal Testing For HIV-1-infected patients with markedly reduced numbers of CD4 lymphocytes, the CD4 cell number is not a good prognostic marker.41,42 To investigate if levels of sCD14 might give predictive information concerning survival, some of the HIV-1-infected patients were tested longitudinally. Twenty-six patients were included in the study when their blood CD4 cell numbers decreased to less than 100 × 106/L. Sera from the HIV-1-infected individuals were collected at different time points, and the patients were divided into two groups: one group of the patients who died during the study period (up to 6 months after the last serum collection; n = 14) and a second group of the patients who survived the same period (n = 12). As shown in Fig 3, the patients who died had a significant increase in sCD14 per time unit compared with the patients who survived. Patients in both groups had similar values for decrease in CD4 lymphocyte number per time unit (Fig 4). At the time of inclusion, survivors and nonsurvivors did not differ significantly in serum sCD14 concentrations (nonsurvivors, 4.01 µg/mL [3.55 to 4.76 µg/mL]; survivors, 3.95 µg/mL [3.31 to 4.92 µg/mL]). They also did not differ significantly in CD4 lymphocyte numbers (nonsurvivors, 43 × 106 cells/L [19 to 63 × 106 cells/L]; survivors, 52 × 106 cells/L [43 to 68 × 106 cells/L]). However, at the last blood sampling, nonsurvivors had significantly higher sCD14 values (6.07 µg/mL [4.58 to 9.67 µg/mL]) compared with the inclusion sample (P = .001), and the number of blood CD4 lymphocytes was also significantly lower (15 × 106 cells/L [9 to 31 × 106 cells/L]) than at the first sampling time point for these patients (P = .003). In contrast, the surviving patients did not have a significant difference in sCD14 concentrations at the last time point (4.25 µg/mL [3.74 to 5.24 µg/mL]) compared with the time of inclusion, whereas the CD4 cell numbers also in these patients were significantly depressed at the last sampling time point (19 × 106 cells/L [11 to 24 × 106 cells/L]) compared with the first (P = .01). Additionally, at the last sampling time point, the nonsurviving patients had significantly higher serum sCD14 concentrations than the patients who survived the study period (P = .008), whereas there were no difference between the two groups in the number of blood CD4 cells.
Viral and Mycobacterial Components Stimulate Monocytes to the Release
of sCD14 In Vitro
Components From M avium Stimulate Monocytes Via the CD14
Pathway
In the present study, we show that there is a marked increase in serum
concentrations of sCD14 in all clinical stages of HIV-1 infection, with
the highest levels in the AIDS group. Particularly high levels were
found in patients with ongoing disseminated MAC infection. Furthermore,
increased levels of sCD14 were significantly correlated with the degree
of immunodeficiency and HIV-1 replication, as measured by number of
blood CD4+ lymphocytes and plasma HIV-1 copy numbers,
respectively. Also, we found a strong correlation between sCD14 and
sTNFR, earlier shown to be important immunological prognostic markers
both in HIV-1 infection32 as well as other
diseases.46,47 The fact that the number of HIV-1 RNA copies
in plasma also showed a highly significant correlation to sCD14 serum
concentrations (Fig 3) further highlights that sCD14 serum
concentrations reflect disease activity and viral load.
Submitted August 25, 1997;
accepted May 5, 1998.
The authors thank Mari Sørensen and Bodil Lunden for outstanding
technical assistance.
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Abstract
Introduction
Abstract
(TNF), soluble TNF
receptors (sTNFR), and neopterin in sera from HIV-1-infected
patients.
70°C until assaying for sCD14. Informed consent for blood
sampling was obtained from each patient.
) and patients who died during the study
period (n = 14, 
). When using linear regression analysis,
variations in sCD14 serum concentration and blood CD4 lymphocyte number
could be analyzed and expressed as changes per time unit (100 days).
The results showed increasing sCD14 levels in the patents who died and
relatively stable levels in the surviving patients (P < .001 comparing the 2 groups). In contrast, both nonsurvivors and survivors
had similar decreasing number of CD4 lymphocytes in blood during the
study period. Shown are medians with corresponding 25 to 75 percentiles.
) and blood CD4 lymphocyte
number (--) for 6 patients are shown. Patients A (with MAC
infection), B (with disseminated Kaposi's sarcoma [KS]), and C (MAC
infection) died during the study period and all had increasing sCD14
values and decreasing number of blood CD4 lymphocytes. Patients D (no
clinical events), E (with disseminated cutaneous Herpes simplex virus
type 1 infection), and F (no clinical events) survived the study period
and all had relatively stable sCD14 levels and decreasing CD4 cell
numbers. Arrows indicate sampling time point with ongoing clinical
event and CDC classification; death is indicated with a cross for
patients A, B, and C.
) stimulated
monocytes to release sCD14, although not as potently as LPS (+). 0 means unstimulated cells. The mean of duplicates is shown; data are
from one experiment representative of three performed.
