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* Unité de Biologie des Rétrovirus Institut Pasteur, Paris, France;
Unité de Recherche et d’Expertise de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France; and
Cytheris, Vanves, France
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The prevalence of abundant thymic tissue in 50% of HIV-infected adults (5) associated with an increase either of naive T cells (6, 7) or of T cell rearrangement excision circles (TREC) 3 after antiretroviral therapy (ART) strongly suggests an attempt of renewal of the T cell pool by the thymus. However, the extent of thymic activity is also dependent on the stage of the disease, as shown in macaques infected by the SIV (8). Among patients with advanced disease, late thymic failure was suggested by CD4+ T cell counts remaining below normal, despite long-term suppression of viral load (9, 10).
In vivo and in vitro studies highlight the crucial role of IL-7 in thymopoiesis (11, 12, 13, 14). Constitutively produced by the bone marrow, thymus (15), mucosal lymphoid tissues (16, 17), and lymph nodes (18), IL-7 contributes to thymocyte proliferation and survival. Moreover, recent in vitro studies in mice indicate that IL-7 also induces an increase of peripheral expansion of T lymphocytes in relation with an increase in the antigenic capacity of the APCs and in T cell survival (19). In patients with AIDS, the plasmatic level of IL-7 is higher than in healthy donors and has been shown to be inversely correlated with the level of CD4+ T cells (18). This possibly reflects an attempt to restore normal T cell levels, since these high levels of IL-7 decrease under ART when T cell count increases (18). Since IL-7 appears to be critical for both regeneration of the T cell repertoire and peripheral expansion of preexisting T cell clones, it might represent an interesting additive therapy to ART.
However, we have previously shown that IL-7 favors HIV replication in mature CD4+ thymocytes and also sustains survival of these infected cells in vitro (11). We also showed that IL-7 favors replication of X4 vs R5 variants in mature CD4+ thymocytes (20). In vitro studies by other groups suggest that IL-7 might induce HIV replication in naturally infected peripheral mononuclear cells (21) by inducing a state of virus permissiveness in quiescent T lymphocytes (22) and even in naive CD4+ T cells (23), or by inducing expression of latent virus (24). These data incited us to determine whether this cytokine modulates HIV replication in vivo. Therefore, although IL-7 would normally be associated with ART in patients, we tested the impact of IL-7 on T lymphocyte reconstitution and viral load in SIV-infected macaques in the absence of antiviral therapy.
We performed this study in young rhesus macaques to be in a situation of high thymic regenerative capacity and during the asymptomatic phase to avoid the thymus dysfunction observed in advanced disease. Furthermore, treatment of HIV patients is usually started at this stage of the disease.
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Materials and Methods |
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Four young rhesus macaques (2 years old) housed and cared for in accordance with European guidelines were included in this study.
These animals were demonstrated to be seronegative for SIVmac, for simian T cell leukemia virus type 1, simian retrovirus type 1 (type D retrovirus), and herpesvirus B. The animals referred to as number 1 and 2 were uninfected controls and 3 and 4 were SIV-infected animals. The macaques 3 and 4 were inoculated with 10 AID50 (50% animal infective doses) of the pathogenic SIVmac251 isolate (provided by A.-M. Aubertin, Institut National de la Santé et de la Recherche Médicale Unite 544, Strasbourg, France).
Recombinant human (rhIL-7) treatment
All animals (infected and noninfected) were injected s.c. with rhIL-7 (CYT 99 007, an Escherichia coli- derived rhIL-7 supplied by Cytheris, Vanves, France) twice a day at 40 µg/kg for 21 days. In the infected macaques, this treatment was performed 29 wk after infection throughout the asymptomatic phase.
Lymphocyte immunophenotyping and flow cytometry analysis
EDTA-treated blood cells were incubated for 15 min with the conjugated mAbs. Erythrocytes were lysed with the Lysing kit (Beckman Coulter, Fullerton, CA). Samples were then washed and fixed in PBS containing 1% paraformaldehyde. Analysis was performed on 5000 cells. Immunostaining was analyzed using an XL-4C cytofluorometer (Beckman Coulter France). For intracellular labeling, cells were permeabilized with the Cytofix/Cytoperm kit (BD Biosciences, Mountain View, CA) before incubation with mAb Ki67.
Abs used for immunostaining
Cells were immunostained using the following conjugated mAbs: CD20-PE (clone L27), HLA-DR-PE (clone L243), CD8-PerCP (clone SK1), CD4-FITC, or CD4-PE (clone M-T477), CD4-PerCP (clone SK3), and CD62L-PE (clone SK11) from BD Biosciences; CD45RA-FITC (clone 2H4) from Beckman Coulter France; and Ki67-FITC (clone Ki67) from DAKO (Roskilde, Denmark) and IgG1, 
-FITC, PE, PerCP (clone MOPC-21), as negative controls.
Quantification of TREC
The TREC were determined in the sorted CD4+ or CD8+ T cells of the peripheral blood according to a modified technique of Zhang et al., (25). CD4+ or CD8+ T cells were lysed and treated with proteinase K at 200 µg/ml for 1 h at 56°C. The quantification of TREC was performed by real-time PCR. Twenty-five microliters of reaction containing 10 µl of cell lysate (25,000 cells), 0.6 µM primers (sense, 5'-ATC ACT CTG TGT CTA GCT CCC AGC-3'; antisense, 5'-ACT TGC TGA GTT TCA TGA TTC CTC TA-3'), 0.2 µM TaqMan probe FAM-TGC GGG CTC CAT CCT CTC GTG T-TAMRA and PCR Buffer Master Mix 1X (PerkinElmer, Wellesley, MA) containing the polymerase and its cofactors. Thermal cycling conditions consisted of 2 min at 50°C and 10 min at 95°C followed by 40 cycles of 15 s at 95°C and 1 min at 60°C. Amplification of a sequence within the ccr5 gene was used to normalize and quantify the number of cells. The primers used were: sense, 5'-TTC TCT GGA ATC TTC TTC ATC ATC C-3'; antisense, 5'-CAA AGG TGA CTG TCC TGG CTT T-3'; and the TaqMan probe, VIC- AAC ACA GCA TGG ACG ATA GCC AGG TAC C-TAMRA).
Quantification of serum viral loads
The SIVmac serum viral loads were measured by real-time quantitative RT-PCR (26). The standard RNA was obtained from the pGEM-5Zf+ GAG plasmid (provided by A.-M. Aubertin, Strasbourg).
In situ hybridization tissue section
In situ hybridization was performed as previously described with a 35S-labeled RNA nef probe derived from the nef SIVmac142 (27).
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Results |
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Since there had been no previous report on IL-7 treatment in macaques when we started this study, we first had to determine the minimal dose of rhIL-7 and the duration of the treatment necessary to induce a beneficial effect on T cell reconstitution. By extrapolation from the active doses in mice, we tested 40 or 80 µg/kg per day. Eighty micrograms per kilogram per day was shown to be a more efficient dose when used during 3 wk and therefore the reported experiments were performed under these conditions.
Our study was conducted on four rhesus macaques. Animals 1 and 2 were uninfected controls, while 3 and 4 were SIV-infected animals as described in Materials and Methods. Infected animals received rhIL-7 treatment during the asymptomatic phase characterized by a stabilization of the viral load and of CD4+ T cell counts. Before rhIL-7 treatment, macaque 3 exhibited a high viral load (106 RNA copies/ml of serum) and its CD4+ T cell number dropped from 5200/µl of blood (a mean of three samplings) and stabilized around 1800/µl of blood (a mean of four samplings), whereas macaque 4 exhibited a low viral load (103 RNA copies/ml of serum) and its CD4+ T cell number was not significantly modified: from 2200 (a mean of three samplings) to 2120/µl of blood (a mean of four samplings).
Impact of IL-7 treatment on the dynamics of hemopoietic cells
Longitudinal studies were then conducted to evaluate the counts of hemopoietic cells during and after rhIL-7 treatment (as shown in Table I). Whether infected or not, the four macaques exhibited a strong increase in T lymphocyte counts during rhIL-7 treatment which persisted after interruption of the treatment (except for macaque 4 whose T cell count returned to basal level at day 60). In other respects, IL-7-transgenic mice have been previously shown to develop B cell lymphoma (28, 29). We therefore measured the B cell population: individual variability was observed in the B cell counts, but no large increase could be seen following rhIL-7 treatment. A decrease was even observed in macaques 1, 2, and 4. We also studied the other hemopoietic cell populations and we observed a slight modification of the erythrocyte count in the four macaques. In macaque 3, a decrease of the platelets was observed, but the main decrease in the four animals concerned the neutrophils. However, this decrease did not affect the health of the animals and was reversible after the end of the rhIL-7 treatment (see at day 60).
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rhIL-7 increases the absolute number of CD4+ or CD8+ T cells and this increase correlates with that of naive CD4+ or CD8+ T cells
We first evaluated the capacity of rhIL-7 to increase the CD4+ and CD8+ T cell pools in peripheral blood. As shown in Fig. 1a, the number of CD4+ T cells increased (2- to 4-fold) and culminated around 5000 CD4+ T cells/µl in all animals (whether infected or not) and even in the presence of a high viral load (macaque 3). The response persisted at least 35 or 39 days after interruption of the treatment (except for macaque 4 whose T cell count already decreased at 39 days after treatment). However, analysis made 11 wk after the treatment (before the sacrifice of the animals) indicated a return to baseline in all animals (data not shown).
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The correlative increased production of naive CD4+ and CD8+ T cells (CD45RA+CD62L+), shown in Fig. 1, b and d, argues for a central renewal of these cells under rhIL-7 treatment. Of note, the percentage of naive/total CD4+ T cells (macaque 1, 85%; 2, 55%; 3, 83%; and 4, 84%) initially high (over 80%) in three of four of these young animals did not increase much with rhIL-7 treatment (macaque 1, 83%; 2, 73%; 3, 85%; and 4, 92% at day 21) except in macaque 2 which initially exhibited a lower percentage. In contrast, the percentages of naive/total CD8+ T cells were all initially lower than for the CD4+ population (macaque 1, 53%; 2, 37%; 3, 57%; and 4, 60%) and increased with the treatment (macaque 1, 70%; 2, 70%; 3, 79%; and 4, 84% at day 21).
rhIL-7 increases T cell activation and proliferation
It has been recently shown that the human CD4+ T lymphocytes expressing the HLA-DR activation marker specifically proliferate in the presence of rhIL-7 in vitro (30). We thus wondered whether rhIL-7 might up-regulate in vivo this activation marker and whether this activation correlates with the capacity to proliferate, as characterized by the expression of the Ki67 marker. As shown in Fig. 2a, an increase in the absolute number of CD4+HLA-DR+ was observed and was associated with an increase in the absolute number of CD4+Ki67+ cells (Fig. 2b). The percentage of HLA-DR+ or Ki67+ cells among the CD4+ cells indicated that these cells increased at a faster rate than the total CD4+ population. For instance, the HLA-DR+ cells rose from 9, 11, 10, and 7%, respectively, for animals 1, 2, 3, and 4 at days 0–25, 28, and 29 and 15% at the peak of the curve at days 10–14. However, after this time point, the number of the circulating HLA-DR+ and Ki67+ cells declined faster than the total CD4+ (Fig. 1a) or the naive CD4+ T cells (Fig. 1b), suggesting a redistribution of these activated cells to other compartments such as the lymph nodes. It is worth pointing out that in all animals except macaque 3, and at each time point, the number of CD4+Ki67+ slightly exceeded that of CD4+HLA-DR+, suggesting that proliferation might also occur in some non-fully activated cells. However, in macaque 3, characterized by a high viral load, the inverse situation was observed: at each time point, the percentage of Ki67+ cells was lower than that of HLA-DR+, suggesting that these fully activated cells which are competent for HIV replication are primed for apoptosis (as well as bystander cells) and do not end up proliferating.
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rhIL-7 induces a decline of TREC in infected macaques
We also determined the level of TREC among the CD4+ and CD8+ T cells. This level is dependent upon the thymic output but also upon cell proliferation which dilutes these episomal markers. Since IL-7 increases both T cell regeneration and T cell proliferation, it was interesting to determine how the TREC values vary during rhIL-7 treatment.
As shown in Fig. 3, despite the high rate of proliferation due to rhIL-7 treatment, the TREC values were maintained in healthy macaques, arguing therefore for an increase in thymic output. In contrast, we observed a marked decline (day 21) in the TREC values in infected animals. Since the magnitude of the production of naive T cells was presumably the same in the four animals, we can argue that this decline was the result of a higher rate of T cell proliferation. This high level of proliferation was not obvious from the counts of Ki67+ cells (Fig. 2, b and d) but the overall rate of proliferation might have been impaired by the rate of apoptosis due to infection. Therefore, we suggest that this particular decline might be due to an increased rate of transition between naive and memory T cells to compensate for the destruction of activated T cells by infection. Of note, interruption of the treatment at day 21 limits the decrease in TREC numbers.
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In vitro studies indicate a possible induction of virus replication in IL7-treated thymocytes (11) or lymphocytes (21, 23). Furthermore, we noticed that rhIL-7 significantly increased lymphadenopathy. This increase in the size of lymph nodes might be linked to the increased level of cell activation and might lead to an increase in virus replication. Therefore, it was of importance, in view of a possible use of rhIL-7 in humans, to determine the effect of rhIL-7 treatment on the viral load in the serum, lymph nodes, and thymus. As shown in Fig. 4, no significant increase in serum viral load was observed in macaques 3 and 4. Similarly, no increase in viral load was observed in the serum of two older macaques (5 years old) treated with rhIL-7 also during the asymptomatic phase (data not shown). Lymph nodes of macaques 3 and 4 were collected before (at the beginning of the asymptomatic phase, 7 wk after infection) and 11 wk after rhIL-7 treatment. Viral load in the lymph nodes was determined by in situ hybridization for SIVmac nucleic acid. We evaluated the median of the number of infected cells per square millimeter in the paracortical area in three distinct sections of lymph nodes. Viral load in lymph nodes correlated with that determined in the serum: macaque 3 characterized by a high serum viral load exhibited a high number of infected cells (a median of 15 productively infected cells/mm2 which did not increase (9/mm2) after rhIL-7 treatment), whereas very few positive cells (below 1/mm2 irrespective of the treatment) was observed in macaque 4. In conclusion, rhIL-7 treatment did not modify the viral load either in the serum or in the lymph nodes.
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Discussion |
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We report here that IL-7 exhibits the remarkable capacity to increase T cell number in monkeys, in particular by increasing the pool of CD4+ and CD8+ naive T cells. This increase reaches the same level whether the animals have been infected or not. Of note, the CD4+ response persisted for at least 5 wk after interruption of the rhIL-7 treatment. Although the increase in T cells was similar in magnitude to that observed by Fry et al. (31), in contrast to these authors, we observed an increase in activated HLA-DR+ cells. The percentage of these cells among the total CD4+ varied for each animal and was independent of infection. It reached around 30%, which represents an 8-fold increase above normal level. The fact that the kinetics of HLA-DR+ cells correlates with that of Ki67+ cells strongly suggests that these activated cells, mostly memory cells, are those that are able to proliferate in the presence of IL-7.
These data are in agreement with the study of Jaleco et al. (30) who showed that under conditions where the HLA-DR+ cells are removed, purified human CD4+ T cells fail to proliferate in response to IL-7. Several ex vivo studies in humans also indicate that IL-7 does not promote the proliferation of naive T cells (32, 33, 34) except in the case of the immature naive cells of the human cord blood which have been identified as recent thymic emigrants (33, 35). Our conclusions differ from those of Fry et al. (31) who observed an expansion of naive T cells. This difference is probably due to the very high IL-7 concentration (500 µg/kg per day) used by these authors, which presumably leads to the proliferation of some recent thymic emigrants still existing in these young animals. Since we observed that the number of Ki67+ cells slightly exceeded those of HLA-DR+ (except for macaque 3), we cannot exclude the possibility that a few non-fully activated cells might be induced to proliferate. Nevertheless, most of the naive cells did not seem to proliferate and their increased number was probably attributable to de novo generation. The TREC values in the CD4+ and CD8+ T cells, measured in healthy animals, argued for an increase in thymic output since they remained stable despite the high level of peripheral expansion. In contrast, the marked decline in TREC values observed in infected animals might result from an increased rate of transition between naive and memory T cells to compensate for the destruction of the activated cells by infection.
TREC levels in CD8+ cells also decreased, probably because cell death also affects CD8+ cells. For instance, it has been shown that human CD8+ cells are driven to apoptosis by indirect mechanisms following infection (36).
On the basis of TREC values, Fry et al. (31) could not conclude in favor of an increase in thymic function, even in healthy animals, because of the dilution of TREC by a higher rate of cell proliferation in response to a higher dose of IL-7 (500 µg/kg per day).
A recent study by Storek et al. (37) described the impact of IL-7 on CD4+ T cell reconstitution after autologous transplantation of CD34+ cells in baboons. The authors observed a greater increase in memory/effector cells (CD45RAlow/-) than in naive CD4+ T cells (CD45RAhigh). They did not formally study the proliferative capacity of these cells, but they did not conclude in favor of de novo generation of CD4+ T cells because of the lack of higher TREC values in IL-7-treated animals compared with placebo-treated animals. Nevertheless, the lack of difference in TREC values in the presence of peripheral proliferation might again argue for an increased thymic output in IL-7-treated animals.
This T cell increase induced by rhIL-7 suggests a role of circulating IL-7, found in higher levels in HIV patients (18), in slowing down the decline of CD4+ T cells. This interpretation is supported by the fact that, under ART, IL-7 levels decrease along with an increase of thymic function-related markers (38). However, our data indicate that pharmacological doses of IL-7 are required to drastically increase the CD4+ T cell population.
In the perspective of an IL-7 therapy in humans, it is important to make sure that this cytokine does not directly increase the viral load, as might be predicted from in vitro studies (11, 20, 21, 22, 23, 24). Regarding the serum viral load, no increase was observed in the four infected macaques (two young and two old animals) in response to IL-7, irrespective of the absolute value of the viral load at the start of the treatment. Although difficult to compare with our study since it deals with infected monkeys undergoing ART and immunization, the study by Fry et al. (31) concludes of the same lack of effect of IL-7 on the serum viral load. We did not determine the viral load in peripheral CD4+ T cells to limit the volume of blood samples. However, it seems likely that modification in T cells would be reflected in the serum during the 39 days of the experiment and particularly during IL-7 treatment. Besides viral load was also determined in T cells in lymph nodes, and no difference was observed irrespective of rhIL-7 treatment. However, this lack of increase in blood and lymph nodes was observed in a situation where the thymus remained uninfected. We have previously shown that rhIL-7 is able to sustain a viral reservoir in mature thymocytes (39). Therefore, it is not excluded that, in more advanced disease conditions, in the case of viral insult to the thymus, rhIL-7 might indirectly increase the peripheral viral load. Of note, a study by Napolitano et al. (40) concludes that, under conditions of thymus infection in the model of HIV-infected SCIDhu mice, IL-7 does not increase viral replication in thymocytes.
In conclusion, our findings represent an encouraging step toward the use of IL-7 in the treatment of immunodeficiency associated with AIDS in human patients. In particular, an important feature of IL-7 treatment is that it can increase the number of CD4+ T cells even in the presence of the virus (particularly illustrated in the case of macaque 3). This is important not only for an immune reconstitution of infected individuals (who are currently under ART), but even more so in patients who ill-respond to the ART and whose levels of CD4+ T cells continue to decrease.
However, additional experiments are needed to confirm the long-term effects of rhIL-7 and to determine whether it will be necessary to proceed by cycles of treatment, for instance to allow neutrophil regeneration. Given the immunogenicity of the cytokine and the appearance of Abs against rhIL-7 at late time points of the experiments (data not shown), it would be wise to use the simian counterpart of rhIL-7 in studies exploring this effect.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicole Israël, Unité de Biologie des Rétrovirus, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, Cedex 15, France. E-mail address: nisrael{at}pasteur.fr
3 Abbreviations used in this paper: TREC, T cell rearrangement excision circle; ART, antiretroviral therapy; rhIL-7, recombinant human IL-7.
Received for publication February 3, 2003. Accepted for publication August 14, 2003.
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