The occurrence of peripheral blood cytopenia (thrombocytopenia, granulocytopenia, anaemia) and various dysplastic lesions of the bone marrow, which are often associated with HIV-1 infection, together with in vitro impaired survival/proliferation, with or without differentiation capacity of CD34+ haematopoietic progenitor cells (HPC) isolated from HIV-1-infected patients, indicates the presence of a virus-dependent lesion of the HPC compartment. However, the bulk of the available experimental evidence points to the lack of HIV-1 susceptibility of CD34+ HPC, and the virusdependent suppressive effect does not seem to require an HPC active or latent HIV-1 infection [1,2].
Although the mechanism responsible for the HIV-1-induced lesion of the HPC compartment may be multifactorial, a major pathogenetic role appears to be played by the apoptosis of CD34+ HPC, triggered by the interaction of free or virus-associated HIV-1 gp120 glycoprotein with the cell membrane of uninfected CD34+ HPC [3–6], a large subset of which express low amounts of CD4 molecules [7,8]. This event may in turn be associated with increased production of endogenous transforming growth factor (TGF)-β1  through upregulation of TGF-β1 promoter activity . TGF-β1 is a cell cycle blocker that acts on target cells by arresting or delaying cells in the G0/G1 phase of the cell cycle [11,12], as well as by inducing apoptosis .
TGF-β1 has been shown to inhibit telomerase activity in tumour cells . Telomeres are nucleoprotein complexes consisting of tandem arrays of TTAGGG repeats, which are bound to specific proteins and form the end of eukaryotic chromosomes . In normal human cells, telomeres shorten with successive cell divisions and the loss of telomeric DNA may serve as a mitotic clock that signals replicative cell senescence, exit from cell cycle and programmed cell death (apoptosis). Telomerase is required to maintain telomere lengths. Telomerase, an RNA-protein complex, is a reverse transcriptase (RT) that uses its RNA component to specify the addition of telomeric repeats to chromosome ends . In humans, telomerase is expressed only in cells with essentially unlimited replicative potential, such as reproductive cells in ovaries and testes, and is repressed in most somatic cells and tissues [16,17]. Telomerase is highly expressed in cancer tissues [16,17], although, at least in mice, its presence is not required for oncogenic transformation or tumour formation .
The ageing of long-term self-renewing haematopoietic stem/progenitor cells is a process still incompletely known . The recent observation that human HPC express telomerase activity [20,21] suggests a possible mechanism by which their ageing process might be delayed, if telomere length is indeed a mitotic clock regulating replicative potential.
We therefore compared the level of telomerase activity expressed in CD34+ HPC isolated from HIV-1-infected patients with the enzyme levels detectable in the same cell types isolated from normal donors. The influence of in vitro exposure to gp120 or TGF-β1 on telomerase levels expressed by normal human CD34+ HPC was also investigated.
Materials and methods
We studied 11 HIV-1-seropositive (nine men and two women, aged 24–35 years) and 15 HIV-1-seronegative (12 men and three women, aged 26–49 years) subjects, who gave their informed consent according to the 1975 Helsinki declaration. Nine peripheral blood and six bone-marrow samples were obtained from healthy donors. For ethical and clinical reasons, only peripheral blood samples were obtained from the 11 HIV-1-seropositive patients studied. However, circulating HPC are considered more ancestral than their bonemarrow counterparts [22,23].
At the time of sampling, both HIV-1 p24 core antigen and HIV-1 RNA loads were quantified in peripheral blood plasma specimens from all HIV-1-seropositive patients. HIV-1 p24 antigenaemia, after immune complex dissociation with basic treatment, was evaluated using a commercial kit (Vironostika HIV-1 Antigen Microelisa System, Organon Teknika, Durham, North Carolina, USA), and HIV-1 RNA quantification was performed using a commercial isothermal amplification kit (NucliSense, Organon Teknika), according to the manufacturer's instructions.
Isolation of CD34+ HPC
CD34+ HPC were isolated using the CD34 Progenitor Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany). Briefly, light density mononuclear cells were initially isolated by density gradient centrifugation (density, 1.077 g/ml; Ficoll-Histopaque, Pharmacia, Uppsala, Sweden). CD34+ cells were then positively selected from the mononuclear cell population by immunomagnetic activated cell sorting  using the QBEND/10 antiCD34 monoclonal antibody (MAb; Miltenyi Biotech). Isolated CD34+ cells were more than 95% pure, as determined from their positive reactivity to immunofluorescence staining with an anti-CD34 MAb recognizing a different epitope (HPCA-2; Becton Dickinson, Mountain View, California, USA). Purified CD34+ HPC were either immediately assayed for telomerase activity, or pretreated with gp120 or TGF-β1.
The presence of HIV-1 proviral DNA in CD34+ cells purified from HIV-1-seropositive subjects was examined by PCR in samples of 20 000 CD34+ cells amplified using HIV-1 gag-specific primers SK38/SK39, following a previously described procedure  with a sensitivity of 10 proviral copies in a background of 104 cells. Positive controls were represented by H9 and Jurkat T-cell lines chronically infected with HIV-1, and negative controls were represented by PCR runs including all reagents except DNA.
Telomerase activity was measured by a PCR-based telomeric repeat amplification protocol (TRAP) [25,26] using the TRAPeze Telomerase Detection Kit (Oncor, Inc., Gaithersburg, Maryland, USA). Briefly, 3-[(3-cholamidopropyl)-ethylammonio]-1-propane-sulfonate (CHAPS) detergent lysis buffer extracts were prepared from isolated bone-marrow and peripheral blood CD34+ HPC. Protein concentrations were determined using the Bradford assay (Bio-Rad Laboratories, Milan, Italy) with bovine serum albumin as a standard, and 0.3 µg proteins were added to each reaction mixture  containing a TS (telomerase substrate) primer which was [γ32P]-labelled at the 5′-end using [γ32P]-ATP (Amersham, Milan, Italy) and T4 polynucleotide kinase (Pharmacia Biotech, Uppsala, Sweden), a mixture of TRAP primers, and Taq DNA polymerase in a final volume of 50 µl.
The reaction mixture was maintained at 30°C for 30 min to allow the telomerase to catalyse the addition of a number of telomeric repeats (CCTTAG) onto the 3′-end of the oligonucleotide substrate (TS) and then was immediately transferred at 80°C to inactivate telomerase. The extended products were then amplified by 25 cycles of PCR, with a 30 sec denaturation step at 94°C, 30 sec annealing step at 50°C, and 45 sec extension step at 72°C, using a 9600 Perkin Elmer thermocycler (Perkin Elmer, Monza, Italy). The amplified products (a ladder of products with six base increments, starting at 50 nucleotides) were resolved by polyacrylamide (9%) gel electrophoresis, run at 2500 V for 2 h at 50°C using a Genom LR instrument (Beckman Analytical, Milan, Italy). Finally, gels were dried and the TRAP products visualized by autoradiography (Hyperfilm-MP, Amersham). Positive telomerase controls consisted of human epithelioid tumour HeLa cell line extracts [Cell Bank, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia (IZSLE), Brescia, Italy], whereas negative controls consisted of human embryo diploid pulmonary fibroblast PEU cell strain extracts (Cell Bank, IZSLE), and CD34+ HPC extracts were pretreated with RNase A (Pharmacia Biotech) used at 5 µg/0.3 µg of proteins for 1 h at 37°C. PCR amplification controls included internal (TRAPeze kit) control oligonucleotides K1 and TSK1, which, together with TS, produced a 36 base-pair band in every lane in order to rule out the presence of Taq DNA polymerase inhibitors in cell extracts, and TRAP assays performed with CHAPS lysis buffer substituted for cell extracts.
TRAP reaction were quantified as follows: the autoradiographic signal intensity of each band of the TRAP product ladders was measured individually using an image analyser (UVP Image Store 7500, Ultra Violet Products Ltd, Cambridge, UK) in combination with Gel Works 1D Gel Analysis software (Ultra Violet Products Ltd) and corrected for background levels. The corrected signals of the products in each lane were then summed to yield arbitrary units of activity. The relative specific telomerase activity in each cell extract was expressed as a percentage of the specific activity obtained with HeLa cell extracts run in the same experiments. All experiments were performed in triplicate.
Telomerase assay in cells pretreated with gp120 or TGF-β1
In order to evaluate the influence of either HIV-1 envelope glycoprotein gp120 or TGF-β1 on the levels of telomerase expressed by HPC, different aliquots of 1 × 106 CD34+ HPC isolated from three bone-marrow and five peripheral blood samples from healthy HIV-1-seronegative donors were washed three times in Iscove's modified Dulbecco's medium (IMDM; Gibco, Grand Island, New York, USA) supplemented with 10% of fetal calf serum (FCS; Gibco), pelletted in 1.5 ml Eppendorf tubes and resuspended in 1 ml IMDM plus 10% FCS. Various aliquots of all cell suspensions were then added with 1 µg recombinant gp120 (rgp120; American Biotechnologies, Cambridge, Massachusetts, USA). In addition, different aliquots of the cell preparations obtained from peripheral blood samples were added with 10 ng recombinant TGF-β1 (rTGF-β1; R&D Systems, Inc., Minneapolis, Minnesota, USA). All cell preparations were incubated for 2 h at 37°C, and washed using low speed centrifugation, resuspended in 1 ml fresh growth medium supplemented with 1 ng/ml interleukin-3 (Genzyme, Cinisello Balsamo, Milan, Italy) and incubated at 37°C for up to 72 h. At the end of the incubation time, CD34+ HPC exposed to either rgp120 or rTGF-β1, together with duplicate mock-treated control cell cultures, were studied for the presence of telomerase activity, as described above. Purity and immunological specificity of rgp120 and rTGF-β1 were checked in our laboratory by Western blot assay using specific MAb (R&D Systems). Moreover, the commercial preparations of rgp120 and rTGF-β1 were found to be free of tumour necrosis factor (TNF)-α and TNF-β by immunoenzymatic assay (R&D Systems) and bacterial endotoxin (Limulus amoebocyte lysate test; Whittaker Bioproducts, Walkersville, Massachusetts, USA).
Cell viability assay
The viability of cells exposed to either rgp120 or rTGF-β1 was checked at the end of the incubation period by trypan blue dye exclusion assay. At the same time, cell extracts of four out of five samples isolated from peripheral blood of healthy donors were also analysed (using standard procedures, with an Olympus AU 5200 automatic analyser, Merck, Darmstadt, Germany) for levels of lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) and creatine kinase, in comparison with untreated control cell preparations.
The mean of the values ± SD for different experiments are shown. Significant differences between groups were determined using either the Mann-Whitney test, or the two-tailed Student's t test for paired samples.
HIV-1-seropositive patient study population
Clinical and virological data characterizing the patients enrolled in the study are shown in Table 1. The patients were in different stages of disease, ranging from stages A1 to C3 of the Centers for Disease Control and Prevention classification . All patients were viraemic, with an RNA viral load range of 100–33 000 HIV-1 RNA copies/ml plasma, with no relationship between RNA viral load and disease stage. Only three patients presented a detectable antigenaemia, with p24 antigen values ranging from 16 to 100 pg/ml. At the time of the study, only five out of 11 HIV-1-seropositive patients examined were under antiretroviral therapy with various combinations of nucleoside or non-nucleoside RT inhibitors or HIV-1 protease inhibitors. All patients had experienced one or more cycles of antiretroviral therapy with zidovudine.
Telomerase activity in CD34+ HPC isolated from HIV-1-seropositive patients and healthy donors
All CD34+ cell populations isolated from HIV-1-seropositive patients were negative for the presence of HIV-1 proviral DNA (data not shown). All controls of telomerase assays gave the results that were expected. The results of some typical experiments for the determination of telomerase activity are shown in Fig. 1. The results obtained from all HPC populations studied are summarized in Table 2.
CD34+ HPC isolated from either peripheral blood or bone marrow of healthy donors expressed significant levels of telomerase activity, which were sometimes higher than those observed in HeLa cells used as positive controls (Table 2). Moreover, even if peripheral blood CD34+ HPC were considered more ancestral than those isolated from bone marrow [22,23], telomerase levels were apparently lower in peripheral blood than in bone-marrow CD34+ cells of healthy donors, although the difference did not reach statistical significance.
However, CD34+ HPC isolated from the peripheral blood of HIV-1-seropositive patients behaved in a significantly different way (P < 0.001). In fact, these cells did not express any detectable telomerase activity in nine patients, and showed a clearly reduced enzymatic activity in two patients. These results unequivocally demonstrated an inhibited telomerase activity in peripheral blood CD34+ HPC from HIV-1-infected patients that was irrespective of the disease stage, presence of p24 antigenaemia, plasma viral RNA load level, and concurrent antiretroviral therapy.
Telomerase assay in normal CD34+ HPC pretreated with gp120 or TGF-β1
The results of one experiment for telomerase assays in CD34+ HPC isolated from either peripheral blood or bone marrow from healthy donor subjects, maintained for 72 h in culture after exposure to rgp120 or rTGF-β1, are shown in Fig. 2. All the results of this set of experiments are summarized in Table 3.
The results obtained showed that exposure to both rgp120 and rTGF-β1 specifically and significantly reduced telomerase activity with respect to untreated control cell preparations (P < 0.001). The inhibition of telomerase activity after exposure to rgp120 was significantly higher than that observed in the presence of rTGF-β1 (P < 0.05). Under these culture conditions, no significant loss of cell viability was observed at the end of the incubation period in cell preparations exposed to either rgp120 or rTGF-β1. In addition, all cell samples analysed for LDH, GOT and creatine kinase levels showed the same enzyme levels as those present in untreated control cell preparations (data not shown).
Shortened telomeres have been demonstrated in T-lymphocyte subsets of HIV-1-infected patients, and the inferred impairment of their replicative potential has been claimed to be a possible mechanism for the decline of selected lymphocyte populations and the exhaustion of T-cell response [28–30].
Our study was the first to demonstrate severely impaired telomerase activity in CD34+ HPC isolated from HIV-1-infected patients in comparison with the same cell population types isolated from healthy donors. By employing the highly sensitive TRAP assay, all CD34+ HPC samples isolated from either peripheral blood or bone marrow from 15 healthy donors were shown to express high telomerase activity. However, telomerase activity was undetectable in nine and severely impaired in two CD34+ HPC populations isolated from the peripheral blood from 11 HIV-1-infected patients.
The function of telomerase in HPC is somewhat controversial , and there is no consensus on which HPC subpopulation or physiological condition is best suited for enzyme expression [20,21]. In addition, telomerase activity also seems to be present in mature T and B cells [21,31], whereas an ageand proliferation-related loss of telomeric DNA has been observed in haematopoietic stem cells .
Nevertheless, our data, which showed dramatically impaired telomerase levels in CD34+ HPC isolated from the peripheral blood of HIV-1-seropositive patients, unequivocally disclosed an additional phenotypic character of CD34+ HPC in HIV-1-infected patients. These findings may have some relevance in the pathogenesis of lesions in the HPC compartment.
We have also shown that CD34+ HPC isolated from healthy subjects show significantly impaired telomerase activity (P < 0.001) when exposed to rgp120 or, to a lesser extent, TGF-β1. These results may help explain our previous findings that purified normal CD34+ HPC show an impaired survival/proliferation capacity after exposure to heat-inactivated HIV-1 or gp120 [4,6]. They are also consistent with the possible role of endogenous TGF-β1 in mediating the inhibitory effect of either HIV-1 or gp120 [9,10] and the demonstration that TGF-β1 is an inhibitor of telomerase activity . Together, these results point to a possible direct intervention of soluble or virus-associated gp120, as the cause of the severely impaired telomerase activity exhibited by HPC isolated from HPC-1-infected patients. In this respect, we have already demonstrated an early loss of circulating HPC during the course of HIV-1 infection  and a close correlation between the impaired number of circulating HPC and active HIV-1 replication .
The results of our experiments demonstrate severely impaired telomerase expression in uninfected CD34+ HPC isolated from the peripheral blood of HIV-1-infected patients. This finding was irrespective of concurrent antiretroviral therapy; therefore, the possible influence of RT inhibitor therapy on the levels of telomerase activity can be ruled out. At the same time, a long-standing consequence of previous zidovudine treatments seems unlikely. In the Tetrahymena termophila model, zidovudine was one of the least efficient telomerase inhibitors amongst the various nucleoside analogues . In immortalized human cell lines, zidovudine was only effective in significantly reducing telomerase activity when employed directly in the reaction mixture at very high concentrations (50–100 mmol/l) , far beyond the levels that can be reached in HIV-1-infected patients, even with a chronic dosing of 250 mg every 4 h (peak and trough concentrations of 0.6 and 0.16 µg/ml plasma, respectively). In vivo zidovudine has a very short half-life and is rapidly metabolized to 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine, which has no effect as an RT inhibitor. The influence of zidovudine on telomerase function and cell senescence of immortalized mouse fibroblasts is completely reversible after inhibitor removal . Six out of 11 HIV-1-infected patients studied did not receive antiretroviral therapy with RT inhibitors for at least 5 months and the lack of telomerase activity observed in HIV-1-infected patients was irrespective of ongoing antiretroviral therapy. Finally, our results showed that gp120 and, to a lesser extent, TGF-β1 are very efficient inhibitors of telomerase activity (much more efficient, on a molar basis, than zidovudine). All these considerations, in our opinion, suggest that the impaired telomerase activity of CD34+ cells of HIV-1-infected subjects is very likely to be a virus-mediated phenomenon rather than a long-standing consequence of zidovudine therapy.
Therefore, we can conclude that the mechanism underlying the impaired telomerase activity of HPC is likely to involve the interaction of HIV-1 envelope glycoprotein gp120 with the cell membrane, and possibly the upregulation of endogenous TGF-β1 expression. These findings may further explain the severely compromised survival/replication capacities [1,2] and the enhanced propensity to apoptosis  of HPC in HIV-1-infected patients, despite the lack of productive/latent HIV-1 infection [1,2].
Whether endogenous TGF-β1 represents an essential intermediate in the gp120-mediated inhibition of telomerase expression remains to be fully elucidated. Further studies are also necessary to establish the relevance of telomerase in the replicative potential of HPC and the role of its inhibition in the pathogenesis of their altered phenotype during HIV-1 infection. These studies, amongst others, may have profound implications in judging the feasibility of experiments aimed at conferring HIV-1 resistance by genetically engineering haematopoietic stem/progenitor cells.
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Keywords:© 1998 Lippincott Williams & Wilkins, Inc.
Telomerase; haematopoietic progenitor cells; HIV-1 infection; transforming growth factor-β1; gp120