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AIDS:
doi: 10.1097/QAD.0b013e3283298572
Editorial Review

Limited efficiency of endogenous interleukin-7 levels in T cell reconstitution during HIV-1 infection: will exogenous interleukin-7 therapy work?

Rethi, Bencea,b; Vivar, Nancya; Sammicheli, Stefanoa; Chiodi, Francescaa

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aDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

bInstitute of Immunology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary.

Received 13 August, 2008

Revised 2 December, 2008

Accepted 6 January, 2009

Correspondence to Francesca Chiodi, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, S-17177 Stockholm, Sweden. Tel: +46 8 52486315; e-mail: Francesca.Chiodi@ki.se

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Introduction

Interleukin (IL)-7 is a potent survival factor for T cells acting through the maintenance of basic cellular homeostasis (i.e. transport mechanisms and metabolic activity) and the regulation of anti-apoptotic and proapoptotic Bcl-2 family member proteins [1]. IL-7 acts as a costimulatory molecule for T cell activation induced by cognate antigens, stimulates homeostatic peripheral expansion of T cells in response to low-affinity antigens in lymphopenic hosts [2,3] and promotes memory formation [4,5].

Increased IL-7 levels have been detected in conditions characterized by abnormally low T cell numbers, including HIV-1 infection [6–9], idiopathic CD4+ T cell lymphocytopenia [10] or cytoreductive therapies for cancer, autoimmune diseases or bone marrow transplantation [6,11,12]. Associated with these lymphopenic conditions, a negative correlation has been repeatedly observed between serum IL-7 levels and peripheral blood CD4+ T cell counts. These findings contributed to the formulation of a homeostatic model of peripheral T cell regulation predicting that T cell depletion leads to high IL-7 levels, which, in turn, would accelerate T cell regeneration through increased survival and proliferation.

In chronic HIV-1 infection, high IL-7 levels can be observed in the blood predominantly when CD4+ T cell count falls below 200 cells/μl, a late stage of HIV-1 infection when T cells seem to be incapable of spontaneous regeneration and high IL-7 levels may not be sufficient to counteract T cell depletion (Fig. 1) [6,7,9]. Therefore, the regenerative effects of lymphopenia-induced IL-7 in HIV-1-infected individuals remain mostly speculative, based on animal models and in-vitro data. By contrast to endogenously elevated IL-7 levels, using high doses of exogenous IL-7 as a short-term therapy may have beneficial effects on peripheral T cells as suggested by the first human trials. In the present review, we discuss the potential effects of elevated IL-7 levels in T cell restoration and immune activation during HIV-1 infection, with particular emphasis on the mechanisms that may restrain T cell recovery despite the high levels of this cytokine.

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The cellular source for interleukin-7 production during HIV-1 infection

Multiple sources of IL-7 have been described, including bone marrow stromal cells, thymic epithelial cells, dendritic cells, keratinocytes and the intestinal epithelium [1]. Recently, specialized stromal cells – the T zone fibroblastic reticular cells (FRCs) – were identified as the main source of IL-7 in lymph node, and these cells effectively supported T cell survival in vitro, partly by IL-7 production [29]. FRCs might play an important role in peripheral T cell maintenance because of their close contact with circulating lymphocytes. HIV-1 infection leads to an altered structure of T cell niches in lymphoid tissues, disrupted by fibrosis related to chronic immune activation and inflammation [30,31], which may interfere with T cell trafficking within the IL-7-producing reticular cell network and, consequently, the access to IL-7.

To date, the mechanisms that modulate circulating IL-7 levels remain to be clarified. IL-7 levels could increase because of an enhanced IL-7 production in response to lymphopenia, implying a feedback loop in which T cell loss would induce the production of factors that could stimulate lymphocyte repopulation. Antigen-presenting cells (APCs) [9], as well as bone marrow-derived stromal cells [13], have been implicated in inducible IL-7 production. Whether FRCs modulate IL-7 production during HIV-1 infection is yet to be further analyzed, although it has already been indicated that the level of IL-7 production in the lymph nodes might be similar in HIV-1-infected and non-infected individuals [32].

As an alternative scenario, IL-7 may accumulate due to reduced consumption caused by the declining number of IL-7R-expressing cells [2,33]. According to the latter, the production of IL-7 by stromal cells, occurring at a fixed constitutive rate, provides an amount of IL-7 that would be enough to support the survival of a determined number of T cells, limiting, in this way, the size of the lymphocyte pool.

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Regulation of interleukin-7 sensitivity during HIV-1 infection through downregulation of interleukin-7Rα

For a better understanding of the possible effects of high IL-7 doses, reached via the homeostatic response to T cell depletion or administered as part of a T cell regenerative therapy, it is important to analyze which cells are targeted by high IL-7 levels. IL-7Rα, a molecule that comprises the receptor for IL-7 together with the common γ chain, is lost on up to 60–70% of peripheral T cells in HIV-1-infected individuals, and these cells are most probably unable to benefit from high IL-7 doses (Fig. 1) [14–16]. In addition to chronic HIV-1 infection, IL-7Rα downregulation has been detected in chronic hepatitis C virus (HCV) infection [34] and in aged individuals [35].

The IL-7Rα-low T cells mostly include CD8+ T cells that express activation or memory markers, and these cells often lack the CD28 coreceptor molecule, a phenotype previously associated with defective proliferative abilities [14,15]. CD4+ T cells of HIV-1-infected individuals are also characterized by IL-7Rα downregulation [15,17], although to a lower extent than CD8+ T cells. Part of the CD4+IL-7Rα-low T cells probably comprises forkhead box P3+ (FoxP3+) regulatory T cells [36], a population that does not exist in the CD8+ T cell subset [37].

The IL-7Rα-low T cells express lower levels of the anti-apoptotic Bcl-2 molecule compared with the IL-7Rα-high T cell counterpart in the same donors, possibly reflecting altered maintenance strategies for these cells not involving IL-7-mediated Bcl-2 induction [15]. Although T cells of HIV-1-infected individuals, analyzed as a whole without distinguishing IL-7Rα-high and IL-7Rα-low populations, are able to benefit from IL-7-induced survival signals in vitro [15,38], such effects of IL-7 on T cell maintenance are clearly decreased in HIV-1-infected individuals compared with controls [15].

IL-7Rα downregulation accelerated in line with disease progression measured by CD4+ T cell depletion and HIV-1 viremia in several cohorts of HIV-1-infected patients [14–16]. As indicated previously [39,40], antiretroviral therapy (ART) induced only partial restoration of IL-7 sensitivity of T cells. Preserved IL-7Rα levels, however, may be indicative of better CD4+ T cell maintenance following treatment interruption [41].

The mechanism leading to IL-7Rα downregulation during HIV-1 infection is yet unknown. Attempts to explain low IL-7Rα levels as the consequence of a high IL-7 concentration or alternatively, through the specific effect of the Tat viral polypeptide on IL-7Rα expression, have been made [42,43]. These studies, however, ignore the fact that both IL-7 or Tat reduces IL-7Rα level transiently, whereas the low IL-7Rα level is stable when T cells from HIV-1-infected patients are cultured in vitro [15]. Moreover, IL-7 or Tat do not affect IL-7Rα expression on specific subsets of T cells as found when T cells of HIV-1-infected individuals were analyzed [14,15]. In addition to potential regulatory mechanisms specifically targeting IL-7Rα expression in HIV-1-infected individuals, alternative models suggest either the preferential infection of CD4+IL-7Rα-high T cells versus the IL-7Rα-low counterparts [33] or survival advantages for the IL-7Rα-low T cells. It has been previously shown that IL-7 facilitates HIV-1 infection of T cells in vitro [44–48] and, in this way. T cells not sensitive for IL-7 may be better preserved. This scenario was, however, not confirmed by another study showing that CD4+IL-7Rα-low T cells were infected by HIV-1 as efficiently as IL-7Rα-high memory T cells [36]. In any case, a preferential infection model could not explain the robust increase in CD8+IL-7Rα-low T cells during HIV-1 infection [14–16].

The fact that the majority of IL-7Rα-low T cells represent previously activated antigen-specific T cell clones in late differentiation stages in both HIV-infected and elderly individuals suggests that chronic antigenic stimulation may provide a driving force for IL-7Rα downregulation and, at the same time, survival and proliferative signals that are independent of IL-7 [14,15,35]. Expansion of IL-7Rα-low T cells has been suggested to take place in vivo in HIV-1-infected and aged individuals [14,35], suggesting that the increasing number of IL-7Rα-low T cells may not only occur because of the loss of IL-7Rα+ T cell subsets.

Interestingly, studies on mouse with lymphocytic choriomeningitis virus (LCMV) infection supported a scenario when long-term antigenic signals would lead to cytokine-independent but activation-dependent maintenance of antigen-specific T cells. Acute LCMV infection resulted in long-lasting memory T cells maintained by IL-7 and IL-15, whereas, in chronic LCMV infection, antigen-specific T cells were not sensitive for these homeostatic cytokines but were maintained through repeated antigen-specific stimulation [49,50]. Acute LCMV infection in mice lacking CD4+ T cells resulted in a higher ratio of IL-7Rα-low CD8+ memory T cells compared with wild type mice, suggesting that CD4+ T cell depletion in HIV-1-infected individuals may further facilitate IL-7R downmodulation [51].

The association of persistent antigenic signals and IL-7Rα downregulation indicates that T cells, specific for pathogens that the host is unable to clear, will loose the ability to receive survival signals from IL-7. Indeed, a high proportion of T cells specific for HIV-1, HCV, cytomegalovirus and Epstein–Barr virus antigens are IL-7Rα low, whereas IL-7Rα expression is better preserved on T cells specific for vaccinia virus or flu [14,34,52,53]. In aged individuals, T cells with low IL-7Rα expression are typically CD8+CD28 effector memory populations with limited T cell receptor (TCR) diversity, implicating long-term T cell activation as the driving force of IL-7R downmodulation in human aging as well [35]. An increased IL-7 concentration may efficiently improve peripheral T cell maintenance by supporting the IL-7Rα-high naive or transiently activated T cells, whereas T cells already committed to HIV-1 or to other chronic pathogens enter an IL-7-independent differentiation pathway with decreased sensitivity to IL-7.

It is noteworthy that a CD8+ T cell subset was also identified with an apparently naive phenotype that expressed low levels of IL-7Rα [55]. When these cells were cultured in vitro, the IL-7Rα expression readily increased and reached levels comparable to T cells that were originally IL-7Rα high. Such transient downregulation of IL-7Rα on naive T cells might reflect the effect of IL-7 or other common gamma chain cytokines on IL-7Rα gene expression [14,15,56].

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Can the high interleukin-7 levels present during HIV-1 infection support T cell maintenance and proliferation?

A major question regarding the potential actions of IL-7 elevated in response to lymphopenia is whether the IL-7 levels present in T cell-depleted individuals are able to confer more efficient maintenance of T cell counts than baseline IL-7 levels. The serum concentration of IL-7 is in the pg/ml range, and even the highest IL-7 levels observed in T cell-depleted individuals are far beyond the concentrations (usually in the ng/ml range) used to identify IL-7 action on T cells in vitro. Although such a discrepancy is yet to be solved, some assumptions and findings may favor the scenario that IL-7 increase triggered by lymphopenia could indeed influence T cell homeostasis. First, blood is probably not a major source of IL-7, and serum IL-7 likely represents a leakage from solid tissues where IL-7 is produced by stromal cells and APCs. Accordingly, IL-7 measurement in serum may not reflect the absolute cytokine levels available for T cells in vivo but could rather serve as an indicatory tool to detect alterations in IL-7 availability. In addition, IL-7 can be deposited on extracellular matrix proteoglycans, thereby increasing local availability and effectiveness in action [57,58].

The finding that IL-7Rα is transiently downregulated by its own ligand has been interpreted as an altruistic regulatory process, in that T cells receiving signals through IL-7Rα downmodulate the receptor to let other cells benefit from the survival effects of IL-7 [33,56]. Indeed, several studies have demonstrated that IL-7 is available at limited concentrations for T cells, and increased IL-7 levels resulted in elevated T cell numbers and increased T cell reactivity in several animal models [59,60], as well as in humans [61,62]. By contrast increased IL-7Rα expression resulted in decreased T cell numbers in thymus as well as in the periphery, possibly through increased IL-7 consumption [56,63]. These studies indicate that an increase in IL-7 concentration by up to ten-fold, predicted by blood IL-7 measurements in HIV-1-infected individuals, could greatly influence IL-7 actions on T cells.

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Interleukin-7 and T cell regeneration during HIV-1 infection

Although IL-7 is often considered to be a cytokine that might contribute to a better T cell maintenance in HIV-1-infected individuals, such a role of IL-7 has been questioned by several studies. First, longitudinal studies on simian immunodeficiency virus (SIV)-infected macaques [64] and HIV-1-infected individuals [65] showed that the increase in IL-7 levels in response to T cell depletion might be inefficient to counteract T cell depletion, and a potentially beneficial effect of IL-7 on T cell preservation has been observed only in sporadic cases [64,65]. High IL-7 levels in chronically HIV-1-infected individuals are associated with late disease stages and profound CD4+ T cell depletion [6,7,9], a finding that may argue against IL-7-induced T cell recovery. In addition, IL-7 levels were significantly lower in long-term nonprogressors (LTNPs) with stable immune status compared with patients who lost the LTNP status during follow-up [65]. Thus, in LTNPs, a high IL-7 concentration appears to predict an accelerated disease progression, rather than increased T cell maintenance. Therefore, whether indications are available to postulate a role of endogenous IL-7 in T cell regeneration in HIV-1-infected individuals is open to question.

During the natural course of HIV-1 infection, a limited degree of T cell regeneration can be observed in the early stage of infection following the initial control of virus replication; IL-7, elevated during primary infection, may promote this transient increase in T cell numbers. A correlation between baseline IL-7 levels and the efficiency of CD4+ T cell regeneration has been observed when ART was initiated during primary infection [16]. However, because limited information is available about IL-7 regulation during primary infection, different IL-7 levels may not only reflect donor variability, but also a different timing of ART initiation that may obviously influence treatment success.

Although chronic HIV-1 infection leads to progressive T cell death, it is evident that T cell depletion occurs in the presence of a T cell stimulatory mechanism reflected by the increased expression of activation markers and an increased ratio of circulating effector and memory T cells. A potential role for T cell regenerative factors during HIV-1 infection may be indicated by CD8+ T cell expansion that compensates for CD4+ T cell depletion and leads to relatively stable T cell numbers for up to several years [66]. In this scenario, competition might take place between peripheral T cells for shared survival and proliferative factors, and IL-7 may serve as a potential candidate for these functions. Depletion of CD4+ T cells may decrease competition for IL-7, and the increased availability of IL-7 may allow an increase of the CD8+ T cell pool, whereas HIV-1-induced killing mechanisms restrain CD4+ T cell regeneration. The exhaustion of CD8+ T cell regenerative potential due to the acquisition of inhibitory receptors [67,68], replicative senescence [69,70] and the loss of IL-7Rα [14,15,71] may explain why IL-7 levels increase only at late stages of HIV-1 infection – as IL-7 consumer T cells are not regenerated any more – and CD8+ T cell exhaustion may also explain the low efficiency of IL-7 to rescue T cells in patients who progress to AIDS. Initiation of ART in chronically infected individuals may open new possibilities for IL-7-mediated T cell stimulation. In patients responding well to therapy, ART often leads to exacerbated T cell responses against previously asymptomatic infections, a phenomenon termed as immune reconstitution inflammatory syndrome (IRIS) [72]. The hyper-responsiveness of T cells in HIV-1-infected individuals suggests the presence of lymphopenia-associated T cell costimulatory factors, and IL-7 is obviously a potential candidate for such an effect [73].

In addition, it has been reported that baseline IL-7 levels may be indicatory for ART efficiency in improving CD4+ T cell numbers [18–21] or viral control [22,23] in chronically infected patients. Contradictory results, however, indicate a less efficient control on virus replication in donors with higher baseline levels of IL-7 [18]. From these findings, it can be concluded that T cell regenerative processes are detectable during HIV-1 infection, independently or as a result of ART, and IL-7 may act as a T cell stimulatory cytokine in these processes.

As we have already discussed, high IL-7 doses may not contribute to a better control of HIV-1 replication and to stable CD4+ T cell numbers in LTNPs [65]. In other contexts, however, IL-7 might play a role in a more efficient T cell preservation. In rhesus macaques infected with SIV, IL-7 concentrations increased in parallel with progression to AIDS, similarly to human HIV-1 infection. By contrast, SIV infection of sooty mangabeys, a species that tolerates SIV with minimal clinical symptoms, resulted in an early increase in serum IL-7 levels right after the transient CD4+ T cell decline upon primary infection. High IL-7 levels were followed by increased T cell proliferation and CD4+ T cell count stabilization, indicating a possible role for early IL-7 increase in rescuing T cell homeostasis from an irreversible damage [24].

In humans, HIV-2 infection is associated with a better disease prognosis due to the slower rate of CD4+ T cell decline compared with HIV-1 infection. In HIV-2-infected individuals, IL-7 levels are inversely correlated with peripheral CD4+ T cell decline, similar to that observed in HIV-1 infection [74]. IL-7Rα expression in HIV-2 infection was better preserved on several T cell subsets, especially on CD8+ cells [74], and higher IL-7Rα expression of T cells may indicate that more T cells could benefit from increasing IL-7 concentrations. Altogether, SIV infection of sooty mangabeys and HIV-2 infection of humans may represent conditions in which the increase in IL-7 concentrations might contribute to a better stability of peripheral CD4+ T cells.

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High interleukin-7 levels may influence B cell differentiation

In HIV-1-infected individuals, several B cell dysfunctions have been identified, including hyperactivation, priming for apoptosis and increased ratio of immature/transitional B cells in circulation. The direct action of IL-7 on peripheral B cells can be debated because of the undetectable IL-7Rα expression on mature B cells. In addition, IL-7 therapy in primate models or humans did not lead to increased peripheral B cell numbers [61,62,75]. Although there are no indications available for a modulatory effect of IL-7 on B cell numbers during HIV infection, IL-7 has been implicated in the perturbation of B cell differentiation that leads to an increased ratio of circulating transitional B lymphocytes, characterized as CD27–CD10+ B cells with low receptor diversity and weak proliferative abilities upon B cell receptor cross-linking. The ratio of immature/transitional B cells correlated with CD4+ T cell depletion as well as with serum IL-7 levels, indicating that IL-7 may influence the peripheral expansion of CD10+ transitional B cells [76]. It is noteworthy that, in idiopathic CD4+ T lymphopenia, unrelated to HIV-1 infection, the prevalence of immature/transitional B cells in blood correlated positively with serum IL-7 concentrations and negatively with CD4+ T cell counts [10]. It is tempting to speculate that factors produced in lymphopenia, including IL-7, may provide modulatory feedback signals for B cell differentiation, although such mechanisms are yet to be better defined.

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The effect of interleukin-7 on virus replication

IL-7 has been shown to facilitate HIV-1 replication, a finding not confirmed in SIV-infected macaques in vivo but repeatedly observed in vitro in thymocytes, resting T cells and peripheral blood mononuclear cells [45–48]. In addition, IL-7 increased the transfection efficiency of naive CD4+ T lymphocytes using HIV-1-derived vectors [77]. In accordance with the potential effects of IL-7 on HIV-1 replication, high IL-7 levels were associated with rapidly replicating syncytium-inducing HIV-1 strains, characterized by the use of chemokine (C-X-C motif) receptor 4 (CXCR4) as a coreceptor [7,25]. These studies suggested that higher IL-7 doses may somehow facilitate the appearance of syncytium-inducing viral strains and not just passively follow the accelerated T cell depletion associated with the emergence of such variants. Although it remains to be further defined whether higher IL-7 levels predispose to a viral coreceptor switch, patients characterized by syncytium-inducing viral phenotype expressed more IL-7 in the serum than non-syncytium-inducing virus-bearing individuals, even when patients with similar levels of CD4+ T cell depletion were compared [7,25]. IL-7 induced CXCR4 upregulation in T cell cultures [7,78,79], and this property of IL-7 may increase the emergence of CXCR4 using viral strains.

Interestingly, when proviral reactivation was compared with resting CD4+ T cells of the same donors in the presence of IL-7 or the combination of phytohemagglutinin and IL-2, it was found that these signals activated different strains of the same proviral repertoire, providing further indication for the modulatory effects of cytokines on virus evolution in parallel with disease progression [48]. Such strain-specific sensitivity of HIV-1 for IL-7 may contribute to the controversial experimental results demonstrating a positive effect of IL-7 on viral infection and replication in vitro [45–48] and the lack of such an effect in vivo (discussed further below). As the latent HIV-1 reservoir represents a major problem in HIV-1 eradication, the property of IL-7 to induce proviral reactivation in resting T cells has suggested the possibility of using IL-7 as a combinatory tool to increase ART efficiency [48,80]. IL-7 in this scenario would possibly extend ART effects towards the latent pool not sensitive to therapy.

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Fas-mediated T cell apoptosis: a potential feedback mechanism that counteracts T cell stimulation by interleukin-7

Apoptotic signals transmitted by Fas molecules contribute to immunological tolerance by depleting repeatedly activated antigen-specific T cells as well as dendritic cells and activated B lymphocytes [81]. Increased Fas triggering may contribute to T cell depletion in HIV-1-infected patients because the expression of Fas on T cells, the levels of membrane bound and soluble FasL molecules and sensitivity to apoptosis are all increased in parallel with disease progression [82–89]. Fas expression and sensitivity of T cells to activation-induced apoptosis is also increased in non-HIV-1-related lymphopenic conditions induced by cytoreductive therapies [90,91].

Susceptibility for Fas-mediated apoptosis is a hallmark of activated T cells, whereas these cells downregulate the IL-7Rα [4], suggesting that IL-7 and Fas may act at different stages of T cell differentiation. However, in lymphopenic individuals, the increase in IL-7 concentrations and the sensitivity of T cells to Fas-mediated apoptosis coexist, indicating a possible interaction of IL-7 and Fas signals. Indeed, as we and others have shown, IL-7 increases Fas expression on naive and memory T cells and induces a cytoskeleton-dependent Fas polarization on the cell surface [26,27]. T cells, when treated with IL-7, undergo apoptosis upon experimental Fas cross-linking [26,27], and IL-7 increased Fas-mediated apoptosis of CD4+ T cells in HIV-1-infected cell cultures as well [28]. High IL-7 levels in the circulation of HIV-1-infected patients were associated with increased Fas expression on T cells and enhanced sensitivity to Fas-mediated apoptosis [26].

Fas, on the other hand, is a dual-function molecule that stimulates T cell proliferation when triggered on the surface of suboptimally activated T cells. Also, administration of high doses of IL-7 to lymphopenic hosts, as well as to T cell cultures, induces T cell maintenance or restoration rather than apoptosis [59–62], suggesting that IL-7-induced sensitivity to Fas-mediated apoptosis may not ultimately lead to T cell depletion. Indeed, as we showed in a recent study, T cells of HIV-1-infected individuals responded with an enhanced proliferation when Fas triggering accompanied suboptimal TCR signals [92]. IL-7 treatment increased the costimulatory activity of Fas molecules on T cells, suggesting a model in which IL-7 and Fas may promote both apoptosis and proliferation depending on the activation status of the cells (Fig. 2). In this scenario, high IL-7 doses increase the sensitivity to Fas signals in T cells that may be followed by apoptosis when Fas is triggered on nonactivated T cells. By contrast, Fas signals, when induced in T cells weakly activated by low-affinity antigens, may rather contribute to an enhanced proliferation.

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Interleukin-7 administration stimulates T cell expansions in simian immunodeficiency virus-infected macaques

The positive effects of IL-7 on T cell survival and proliferation, as well as the natural increase in serum IL-7 concentrations in response to T cell depletion, suggested that this cytokine could be useful to stimulate T cell regeneration in clinical conditions associated with lymphopenia. When recombinant human or simian IL-7 was administered to SIV-infected macaques, a consistent, but transient, increase in peripheral blood T cell count was detected [59,60,75]. Notably, the doses of IL-7 administered in these studies may significantly exceed in-vivo concentrations, even in lymphopenic individuals, as suggested by the almost complete downregulation of IL-7Rα on peripheral T cells in response to therapy [75]. The numbers of CD4+ and CD8+ naive and memory T cells were evenly increased in the circulation of IL-7-treated animals. The expression of T cell activation markers, human leukocyte antigen-DR, CD25 and Fas, was found to be elevated in some of the studies [59,60,26], reflecting the activated/memory phenotype observed upon homeostatic T cells expansion in lympopenic humans or mice [91,93]. Peripheral expansion of all T cell subsets was evident [59,60,75] and, by using the sj:βTREC ratio, the stimulatory effect of IL-7 on intrathymic proliferation of T cell progenitors was also detected [59]. By contrast to studies conducted with T cell cultures, IL-7 therapy did not induce viral replication in the infected animals [59,60]. The increase in T cell numbers by exogenous IL-7 was transient [59,60,75] and, in line with T cell decline, a neutralizing anti-IL-7 antibody response appeared, indicating potential limitations for long-term IL-7 therapies [59]. The transient nature of T cell stimulation suggests that exogenous IL-7 may serve as a potential supplement for other approaches aiming at long-term T cell regeneration, such as ART for HIV-1-infected individuals, or as an adjuvant improving vaccine efficiency.

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Interleukin-7 therapy during lymphopenic conditions in humans

In many different contexts, the lymphopenic condition induced upon chemotherapy of cancer patients has been correlated with HIV-1-induced immunopathology. Thus, when trying to unravel the potential use of IL-7 therapy to ameliorate T cell regeneration during HIV-1 infection, it is interesting to learn how IL-7 therapy improves the T cell pool in chemotherapy-treated cancer patients. A trial was conducted by administering recombinant IL-7 every third day, eight times in total, to 11 patients with metastatic melanoma and one with metastatic sarcoma [61]. This study indicated that high IL-7 doses induced a consistent but transient increase in both CD4+ and CD8+ T cell counts and a decreased ratio of FoxP3+ regulatory T cells, possibly reflecting the inefficiency of IL-7 to stimulate T regulatory cells characterized by low IL-7Rα expression. Lack of regulatory T cell stimulation by IL-7, in contrast to the effect of IL-2 therapy [94,95], may be an important factor for therapy design when an improved antiviral or antitumor immune response is desired in addition to increasing overall T cell numbers.

Another more detailed study that enrolled 16 individuals with nonhematologic, nonlymphoid cancer confirmed the increase in both peripheral CD4+ and CD8+ T cell numbers in response to IL-7 therapy [62]. Increased peripheral expansion, as measured by Ki67 expression and TREC dilution, upregulated expression of the antiapoptotic protein Bcl-2 and, possibly, an increased egress of newly developed lymphocytes from the thymus may all contribute to the beneficiary effects of IL-7 on peripheral T cell numbers. Importantly, apart from an effect on cell numbers, IL-7 therapy also induced qualitative changes in peripheral T cell repertoire by increasing the ratio of naive cells and by promoting TCR repertoire diversity in four out of six individuals tested and decreasing the ratio of terminally differentiated effector and memory populations as well as regulatory T cells. Two additional ongoing clinical trials, the Adult Clinical Trials Group (ACTG) 5214 and at the Agence Nationale de Recherche sur le Sida et les Hepatitis Virales, on IL-7 administration to HIV-1-infected patients have reported favorable results regarding safety, tolerability and T cell expansion.

Although the initial data are encouraging, questions about long-term benefits of exogenously administered IL-7 remain to be addressed. First, an immediate decrease in T cell numbers has been repeatedly observed (in ACTG 5214 as well as in another study [62]) together with the increase in Fas expression on the surface of peripheral T cells, indicating the activation of T cell-depleting mechanisms by high IL-7 doses. As IL-7 primed T cells to Fas-mediated apoptosis in vitro [26,27], it will be important to analyze whether T cells are lost in IL-7-treated patients through Fas activation and whether therapy can be optimized in order to avoid unnecessary T cell loss. It also remains to be analyzed whether patients benefit from the IL-7-induced T cell boost longer than a few weeks following termination of the therapy or whether, as observed in primates, the IL-7-induced increase in peripheral T cell numbers is only transient. Administration of high IL-7 doses may also increase the risk for autoimmunity as T cells that recognize low-affinity antigens (potentially self-antigens) have the ability to undergo activation and homeostatic expansions. In this respect, a link between lymphopenia and increased risk of autoimmunity has already been recognized [73]. IL-7 has been implicated in joint destruction in rheumatoid arthritis patients [96,97] and in the activation of auto-reactive T cells in a mouse diabetes model [98]. Furthermore, HIV-1 infection is associated with a wide range of autoimmune disorders [99], possibly indicating a further risk of autoimmune reactions boosted by IL-7. An additional complication that might be associated with IL-7 therapy is the induction of an IL-7-specific antibody response, as observed in several of the studies on primates and cancer patients [59,61,62]. However, IL-7-neutralizing antibody responses have not been detected in the first human studies.

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Conclusion

Elevated concentrations of endogenous IL-7 seem to be unable to rescue peripheral T cells when HIV-1-infected patients progress to AIDS. Several factors might contribute to the inefficiency of high IL-7 doses in T cell restoration, including T cell-depleting signals and T cell exhaustion induced by HIV-1, directly or through chronic T cell activation (Table 1). Whether IL-7, when applied at very high doses for a short period as a T cell regenerative therapy, may revert T cell depletion and functional impairments in HIV-1-infected individuals is a question that should be answered by currently ongoing trials.

Table 1
Table 1
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Accelerated aging of T cells reflected by a narrowed TCR diversity, shift from naive cells towards a limited set of effector clones, replicative senescence and the acquisition of inhibitory receptors are all implicated in the immunopathology of HIV-1 infection as well as in other chronic diseases and aging [54,67,69,70,100,101]. Therefore, IL-7 therapy, by increasing peripheral T cell numbers and reversing T cell aging and exhaustion, may have the potential to significantly improve T cell functionality in these conditions.

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Acknowledgements

Bence Rethi, Nancy Vivar, Stefano Sammicheli and Francesca Chiodi contributed to the writing of the text. The work of the authors is supported by grants received from the Swedish MRC, the Swedish International Development Agency (SIDA-SAREC), and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institutet. Francesca Chiodi is a member of the EU Fp6 Network of Excellence Europrise, and Stefano Sammicheli is a fellow of the Fp6 EU Marie-Curie training program on HIV and tuberculosis coinfections. Bence Rethi is supported by the Magyary Zoltan Postdoctoral Fellowship and by the Hungarian Scientific Research Fund (K72532).

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