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Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?
Opinion
TRENDS in Immunology
Vol.25 No.3 March 2004
Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy? Claudio M. Mastroianni, Gabriella d’Ettorre, Gabriele Forcina and Vincenzo Vullo Department of Infectious and Tropical Diseases, La Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy
The current antiretroviral therapy has improved the clinical outcome of HIV-infected patients. However, the drug toxicity, the emergence of drug-resistant HIV variants and the incomplete reconstitution of immune responses underline the need for additional therapeutic strategies, such as cytokine-based therapy. Interleukin15 (IL-15) has a central role in the immune response during HIV infection. Recently, defective production of IL-15 has been found in AIDS patients and it might account for the impairment of natural and adaptive immune responses against HIV. IL-15 is more potent than IL-2 and IL-7 in enhancing the function of HIVspecific CD81 T cells and it is a superior HIV vaccine molecular adjuvant. In this Opinion, we propose that IL-15 could be used for clinical intervention in HIV infection. The introduction of highly active antiretroviral treatment (HAART) has produced substantial clinical benefits to individuals with HIV infection, reducing opportunistic infections, rate of hospitalizations and HIV-associated mortality [1,2]. However, the major limitation of current antiretroviral therapies is the inability to eradicate the virus and to induce a full restoration of immunity against HIV [3,4]. Recently, immunological therapeutic strategies, such as cytokine-based treatment, have been proposed to augment either innate or acquired immune responses in patients with HIV infection [5– 7]. Interleukin-15 (IL-15) is a member of the common g-chain family of cytokines, also including IL-2, IL-4, IL-7, IL-9 and IL-21. It uses the b-subunit of the IL-2-receptor (IL-2R) and its own unique a-chain (IL-15Ra) as crucial signaling components. Unlike IL-2, IL-15 mRNA is present in monocytes, macrophages, dendritic cells (DCs) and many non-lymphoid tissues. IL-15 is produced by antigen-presenting cells (APCs) in the early phase of the immune response to infection and it has an important role in the regulation of innate and adaptive immune-cell functions [8] (Box 1). There are several lines of evidence documenting the increased biological relevance of IL-15 during the course of HIV infection [9]. In particular, the altered production of IL-15 might contribute to the progressive impairment of innate and adaptive immune responses that are only partially restored by antiretroviral therapy [10]. Because of its anti-apoptotic properties and its fundamental role in enhancing survival and function of
natural killer (NK) effector cells and CD8þ T cells, IL-15 has been proposed as immunorestorative agent to boost immunity against HIV [10,11]. In addition, given the ability to maintain the memory CD8þ T-cell compartment, IL-15 could also be useful as molecular vaccine adjuvant [12]. The aim of this Opinion is to highlight recent data about the central role of IL-15 in the immune response during HIV infection and its potential use as an immunotherapeutic agent. IL-15 production during HIV infection The damage to normal cytokine signaling and function is a key factor in the immunopathogenesis of HIV infection [13]. The perturbation of the cytokine network contributes both to the impairment of HIV-specific immune responses and to the increased susceptibility to opportunistic infections. Type 1 cytokines, generally, are decreased with the progression of HIV disease, whereas type 2 cytokines are increased. However, some authors have shown that there are no detectable shifts from Th1 to Th2 cytokine production in HIV infection [14,15]. Little is known in the literature about IL-15 production in HIVinfected individuals. One study indicates that circulating levels of IL-15 were elevated during HIV infection [16]. Conversely, in another investigation the amount of IL-15 secreted by peripheral blood mononuclear cells (PBMCs) Box 1. Important immunological properties of IL-15 † Interleukin-15 (IL-15) has an essential role in natural killer (NK)-cell development, differentiation and maturation. IL-15 activates NK-cell proliferation, cytotoxicity and cytokine and chemokine secretion. † IL-15 is important in the in vitro activation of the functional properties of neutrophils, by delaying apoptosis and enhancing chemotaxis and fungicidal activity. † Monocytes, macrophages and dendritic cells are a major source of IL-15 production. IL-15 exerts autocrine activity on monocytes by inducing IL-8 and monocyte chemoattractant protein-1 (MCP-1) secretion. † IL-15 induces cell proliferation and polyclonal antibody secretion in B cells. † IL-15 is a potent growth factor for T cells, promoting activation and proliferation. IL-15 stimulates human Th1-cell differentiation and acts as a potent chemoattractant for T lymphocytes, regulating T-cell trafficking in vivo. † IL-15 inhibits in vitro T-cell apoptosis and in vivo anti-Fas-induced apoptosis. † IL-15 enhances the survival, activation, interferon-g (IFN-g) production and cytotoxicity of CD8þ T cells and has an important role in regulating CD8þ T-cell homeostasis in vivo.
Corresponding author: Claudio M. Mastroianni ([email protected]). www.sciencedirect.com 1471-4906/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2004.01.002
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from HIV-infected individuals on stimulation with bacterial strains was reduced if compared with HIV-seronegative donors [17]. In a recent study, Ahmad et al. extensively evaluated the production of IL-15 in HIVinfected patients by assessing the circulating levels of cytokine as well as the ability of PBMCs to release IL-15 in response to stimulation by herpes simplex virus-1 (HSV-1) [10]. In HIV-infected patients, serum levels of IL-15 were significantly decreased compared to healthy controls. In addition, there was an impairment in IL-15 production by PBMCs on stimulation with HSV-1, especially in the advanced stage of the disease. These data are in agreement with our previous results about the production of IL-15 by stimulated PBMCs from various groups of HIV-infected patients, including those receiving antiretroviral drugs [18]. PBMCs from antiretroviral-naı¨ve patients with low CD4þ T-cell counts and patients with treatment failure were defective in their ability to release IL-15 in response to opportunistic pathogens. However, patients with a sustained increase in CD4þ count after antiretroviral therapy showed an enhanced production of IL-15. Similarly, high plasma levels of IL-15 were found in chronically HIV-infected patients, controlling viral replication after structured treatment interruption [19]. A defective production of IL-15 has been also found in a murine model of AIDS and it might account for the high susceptibility of these mice to mycobacterial infections [20]. Mice genetically deficient in IL-15 displayed a marked reduction in NK- and CD8 T-cell function, suggesting a crucial role for this cytokine in the generation of both innate and acquired effector arms of immunity [21]. Taken together, these data suggest that HIVþ PBMCs are compromised in their ability to release IL-15 in response to viral, bacterial or fungal stimuli. This deficit could lead to the damage of natural as well as adaptive immune responses during HIV infection.
…the altered production of IL-15 might contribute to the progressive impairment of innate and adaptive immune responses [during the course of HIV infection]… The production of IL-15 is impaired only at posttranscriptional level because PBMCs from HIV-infected patients constitutively express increased levels of the IL-15 gene. Increased expression of IL-15 mRNA was also found in tissues during primary simian immunodeficiency virus (SIV) infection [22]. In addition, elevated levels of mRNA for IL-15Ra were also observed in PBMCs during primary HIV infection (PHI) [23]. In such a context, IL-15 seems to be involved in the generation of proliferating CCR5þ T cells, by inhibiting spontaneous apoptosis in association with upregulation of Bcl-2 expression. The IL-15 effect on CCR5þ T cells during PHI seems to be crucial for productive HIV infection and the establishment of latently infected cells. www.sciencedirect.com
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Several cell types other than PBMCs might be involved in the dysregulated production IL-15 during HIV infection. DCs are functionally relevant sources of IL-15 in the context of immune responses and are potent APCs that are capable of activating and expanding both effector CD8þ T cells and helper CD4þ T cells [24,25]. Alterations in DC number and function could be an essential factor in the development of T-cell functional impairment in HIV infection [26]. HIV-infected DCs can exhibit changes in immunoregulatory cytokines that modulate T-cell responses and the expression of T-cell stimulatory and co-stimulatory molecules. Future studies are needed to investigate the production of IL-15 by HIV-infected DCs and the role of DC-derived IL-15 in driving the outcome of HIV-specific T-cell responses. IL-15 as an immunotherapeutic agent in HIV infection The ability of IL-15 to modulate innate and specific immune responses against HIV supports the clinical interest in using this cytokine as an immunorestorative agent during HIV infection (Figure 1). HIV-specific CD8þ T-cell responses have a central role in controlling HIV infection and disease progression. Recent data indicate that NK cells are able to control HIV replication to the same extent as CD8þ T cells [27]. In HIV-infected individuals, in vitro treatment with IL-15 improves neutrophil functional activities, increases survival and functions of NK cells and promotes the expansion of HIV specific T lymphocytes [9,28,29]. IL-15 is important in the maintenance of the memory pool of CD8þ T cells and it is efficient in enhancing survival and effector functions of HIV-specific CD8þ T cells [11,30]. Indeed, this cytokine has a potent inhibitor effect on spontaneous and CD95 (Fas)induced apoptosis of effector memory HIV-specific CD8þ cells. The mechanism of inhibition is unknown and it probably involves upregulation of intracellular level of Bcl-2 [23]. IL-15 also improves the long-term survival and effector functions of HIV-specific CD8þ T cells by increasing ex vivo cytotoxicity and interferon-g (IFN-g) production [11]. A comparative evaluation in HIV-infected pediatric patients of CD8þ T-cell responses, after in vitro treatment with IL-2, IL-7 and IL-15, showed that IL-15 is the most potent cytokine in augmenting HIV-gag-specific CD8þ T-cell responses. These findings suggest the importance of IL-15 in boosting HIV-specific immunity [31]. IFN-g is a key cytokine involved in the regulation of innate immunity and adaptive CD4þ Th1 immune responses. Therefore, the identification of cytokines that contribute to the production of IFN-g during the early stages of viral infection is an issue of great importance. IL-15, in synergy with IL-21, seems to be a potent upregulator of IFN-g gene expression in human NK and T cells by activating the Janus kinase–STAT (signal transducer and activator of transcription) pathway [32]. During HIV infection, IL-15 could have an important role in the immune restoration by maintaining and/or augmenting IFN-g production from NK cells and HIV-specific CD8þ T cells. One of the problems in using cytokines in vivo as immunotherapeutic agents for the management of HIV infection is the potential activation of HIV replication.
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Macrophage
DC IL-15
IL-15 Th0 cell
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ThP cell IL-15
IFN-γ
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Th1 cell CD8+ T cell
IFN-γ IFN-γ
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TRENDS in Immunology
Figure 1. Central role of interleukin-15 (IL-15) in the immune response during HIV infection. In response to antigens, dendritic cells (DCs) and other antigen-presenting cells (APCs), such as macrophages, produce IL-15, which stimulates interferon-g (IFN-g) production in natural killer (NK) cells and T lymphocytes. IL-15 induces Th1 T-cell differentiation, shifting the subsequent adaptive T-cell response toward Th1. In addition, IL-15 has a key role as activator of NK activity and the cytotoxic T-lymphocyte (CTL) response. HIV infection inhibits IL-15 production, decreasing the Th1 response and NK and CTL activity. IL-15 might be useful as immunotherapeutic agent to augment NK and CTL activity and to restore cell-mediated immune responses against HIV. Abbreviations: ThP, T helper precursor.
Therefore, the possible clinical use of IL-15 requires careful evaluation of the effect on HIV replication [33,34]. Data from different laboratories indicate that IL-15 has an additional advantage over other cytokines, such as IL-2, because it seems not to induce HIV replication in vitro [17,18].
…clinical use of IL-15 requires careful evaluation of the effect on HIV replication. Recent investigations suggest that Th1 cytokines could be proposed as vaccine molecular adjuvants. IL-12 can be useful as a DNA vaccine adjuvant in a herpes mouse model [35]. A recent study compared the usefulness of IL-2 and IL-15 as HIV vaccine components for inducing both longlasting cellular and humoral immune responses [12]. Coadministration of HIV vaccine vectors with vaccinia viruses (VVs) expressing IL-15 induced long-lasting cellular immunity and the T-cell mediated immunity evoked by IL-2 as vaccine adjuvants was short-lived. www.sciencedirect.com
This effect is mainly a result of the fact that IL-15 is implicated as a central player in CD8 memory T-cell homeostasis. In this regard, the administration of the VVs expressing IL-15 induces an increased number of memory CD8þ T cells expressing IL-15Ra and CD8þ T cells persist for several months showing a high proliferative response to IL-15 in vivo and in vitro. These findings, in agreement with previous studies, indicate that IL-15 can maintain memory CD8þ T-cell proliferation in an antigen-independent manner [36,37]. The potential toxicity and adverse effects of IL-15 must be kept in mind when considering administration of such a cytokine to humans [9,38]. The known properties of IL-15 as a potent antigen-independent stimulator might account for the development of direct inflammatory side effects. Because IL-15 promotes T-cell chemotaxis, adhesion molecule expression and chemokine production, it is conceivable that this cytokine could be involved in the development of antigen-induced immunopathology [39]. Studies on SCID (severe combined immunodeficiency) mice indicate that in vivo neutralization of IL-15 before the lipopolysaccharide (LPS) priming phase significantly reduces lethality in the generalized Shwartzman reaction [40]. In addition, leukemia, like other cancers, can be a
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result of chronic stimulation by proinflammatory cytokines. In particular, IL-15 transgenic mice that overexpress IL-15 show early expansion in NK and CD8þ Tcells and later develop fatal lymphocytic leukemia [41]. Given the potential toxicity of IL-15, the use of this cytokine in humans requires careful monitoring of such side-effects.
…IL-15 can maintain memory CD81 T-cell proliferation in an antigenindependent manner. A crucial issue is the identification of useful surrogate markers to assess the clinical efficacy of IL-15 in HIV infection. HIV-infected patients receiving recombinant IL-2, a cytokine with similar properties to IL-15, frequently exhibit a significant elevation in their absolute CD4þ T-cell count; however, the clinical benefit of such an increase is not yet established [42]. In a recently published study, the nadir CD4þ cell count emerged as a significant predictor of clinical response to intermittent subcutaneous administration of IL-2 [43]. Based on these findings, we believe that only future clinical trials will provide useful information to identify surrogate markers assessing the beneficial effects of IL-15 therapy in HIV infection. Another point to clarify is the stage of infection when IL-15 should be used. In our opinion, we believe that IL-15 should be administered early during the course of HIV infection when T cells maintain their ability to respond to such a cytokine. In the advanced stage of the disease, HIVspecific CD8þ T cells could reach replicative senescence or clonal exhaustion as the result of chronic immune activation. In such a context, HIV-specific CD8þ T cells might have a reduced proliferative capacity to respond to antigens even after exogenous administration of IL-15 [44]. IL-15 and immune control of HIV infection Although several studies suggest that the immune system has an important role in the response against HIV, the virus persists in the host, leading to disease progression and the development of AIDS. The reasons for a lack of effective immune control are still not completely understood. Several factors, including immune exhaustion, replicative senescence of CD8þ T cells, lack of adequate Th-cell function, immune escape, ineffective cytotoxic T-lymphocyte (CTL) responses in vivo and viral reservoirs, must be taken into consideration in explaining this phenomenon [44 –47]. It has been argued by some authors that HIV infection could lead to an acceleration of the senescence or decay of the immune system, resulting in immune exhaustion and the development of AIDS [48]. In such a context, the use of IL-15 or other cytokines as immunorestorative agents could be potentially harmful, considering the effect on T-cell expansion and differentiation. IL-15 might contribute to the overactivation and exhaustion of CD8þ T cells, leading to premature ageing of the immune system. Recent lines of evidence suggest that the reason for failing immune control of HIV infection could be ascribed www.sciencedirect.com
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to the impaired maturation of CD8þ T cells [49]. In particular, during the progression to AIDS, HIV-specific T cells do not fully differentiate to the CD272 effector stage. However, in HIV-infected long-term non progressors, T cells have a CD272 phenotype with strong direct cytolytic capacity related to the high expression of effector molecules, such as granzymes and perforin [50]. Factors that influence the HIV-specific CD8þ T-cell differentiation are not fully elucidated. IL-15, which is essential for the expansion and maintenance of CTLs, could play an important role during HIV infection. On this basis, the use of IL-15 therapy could be beneficial for the full maturation of effective HIV-specific CD8þ T cells, thus driving the immune control of infections. Concluding remarks The defective production of IL-15 in HIV-infected individuals might contribute to the impairment of NK and CD8þ T-cell function. In vitro administration of IL-15 inhibits CD95 (Fas)-induced apoptosis and enhances the survival and function of HIV-specific CD8þ T cells, indicating the importance of this cytokine in the restoration of HIVspecific immunity. In addition, IL-15 seems to be more potent than IL-2 and IL-7 in augmenting CD8þ T-cell responses. Because of its long-lasting effect on cellular immunity, IL-15 might represent an optimal cytokine adjuvant for an effective vaccine against HIV. However, the potent ability of IL-15 to induce survival and proliferation of T cells should be assessed against the possible detrimental effect of increased immune activation and accelerated immunesenescence. In addition, the use of IL-15 in humans requires careful monitoring for possible inflammatory side effects. The development of immune-based strategies for the treatment of HIV infection remains a great challenge. We propose that IL-15, through its ability to stimulate both innate and adaptive immune responses, could be used as an immunotherapeutic agent in HIV disease. Therefore, studies examining the safety and efficacy of IL-15 in animal models of HIV infection, such as SIV infection, should be strongly encouraged. References 1 Van Sighem, A.I. et al. (2003) Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS 17, 2227 – 2236 2 Mocroft, A. et al. (2003) Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 362, 22 – 29 3 Carcelain, G. et al. (2001) Reconstitution of CD4þ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr. Opin. Immunol. 13, 483 – 488 4 Valdez, H. (2002) Immune restoration after treatment of HIV-1 infection with highly active antiretroviral therapy (HAART). AIDS Rev. 4, 157 – 164 5 Autran, B. (2002) Strategies toward restoration of immunity to HIV. AIDS 16, 4 – 6 6 Letvin, N.L. and Walker, B. (2003) Immunopathogenesis and immunotherapy in AIDS virus infections. Nat. Med. 9, 861 – 866 7 Pett, S.L. and Kelleher, A.D. (2003) Cytokine therapies in HIV-1 infection: present and future. Expert Rev. Anti-Infect. Ther. 1, 83 – 96 8 Lodolce, J.P. et al. (2002) Regulation of lymphoid homeostasis by interleukin-15. Cytokine Growth Factor Rev. 13, 429 – 439 9 Fehniger, T.A. and Caligiuri, M.A. (2001) Interleukin 15: biology and relevance to human disease. Blood 97, 14– 32
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10 Ahmad, R. et al. (2003) Studies on the production of IL-15 in HIVinfected/AIDS patients. J. Clin. Immunol. 23, 81 – 90 11 Mueller, Y.M. et al. (2003) IL-15 enhances survival and function of HIVspecific CD8þ T cells. Blood 101, 1024 – 1029 12 Oh, S. et al. (2003) Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc. Natl. Acad. Sci. U. S. A. 100, 3392– 3397 13 Fauci, A.S. (1996) Host factors and pathogenesis of HIV-induced disease. Nature 384, 529– 534 14 Tanaka, M. et al. (1999) Reduction in interleukin-2-producing cells but not Th1 to Th2 shift in moderate and advanced stages of human immunodeficiency virus type-1-infection: direct analysis of intracellular cytokine concentrations in CD4þ and CD8þ T-cells. Scand. J. Immunol. 50, 550 – 554 15 Douglas, S.T. et al. (2003) TH1 and TH2 cytokine mRNA and protein levels in human immunodeficiency virus (HIV)-seropositive and HIVseronegative youths. Clin. Diagn. Lab. Immunol. 10, 339 – 404 16 Kacani, L. et al. (1997) Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. Clin. Exp. Immunol. 108, 14 – 18 17 Chehimi, J. et al. (1997) IL-15 enhances immune functions during HIV infection. J. Immunol. 158, 5978– 5987 18 d’Ettorre, G. et al. (2002) Interleukin-15 in HIV infection: immunological and virological interactions in antiretroviral-naı¨ve and -treated patients. AIDS 16, 181 – 188 19 Amicosante, M. et al. (2003) Levels of interleukin-15 in plasma may predict a favorable outcome of structured treatment interruption in patients with chronic human immunodeficiency virus infection. J. Infect. Dis. 188, 661 – 665 20 Umemura, M. et al. (2001) Impaired IL-15 production associated with susceptibility of murine AIDS to mycobacterial infection. J. Leukoc. Biol. 69, 138– 148 21 Kennedy, N.K. et al. (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771 – 780 22 Caufour, P. et al. (2001) Longitudinal analysis of CD8þ T-cell phenotype and IL-7, IL-15 and IL-16 mRNA expression in different tissues during primary simian immunodeficiency virus infection. Microbes Infect. 3, 181 – 191 23 Zaunders, J.J. et al. (2003) Polyclonal proliferation and apoptosis of CCR5þ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2. J. Infect. Dis. 187, 1735– 1747 24 Mattei, F. et al. (2001) IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J. Immunol. 167, 1179 – 1187 25 Liu, Y.J. et al. (2001) Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259– 262 26 Barron, M.A. et al. (2003) Influence of plasma viremia on defects in number and immunophenotype of blood dendritic cell subsets in human immunodeficiency virus 1-infected individuals. J. Infect. Dis. 187, 26 – 37 27 Kottilil, S. et al. (2003) Innate immunity in human immunodeficiency virus infection: effect of viremia on natural killer cell function. J. Infect. Dis. 187, 1038– 1045 28 Mastroianni, C.M. et al. (2000) Interleukin-15 enhances neutrophil functional activity in patients with human immunodeficiency virus infection. Blood 96, 1979– 1984 29 Naora, H. et al. (1999) Enhanced survival and potent expansion of the natural killer cell population of HIV-infected individuals by exogenous interleukin-15. Immunol. Lett. 68, 359 – 367 30 Mueller, M.Y. et al. (2003) IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4þ and CD8þ effectormemory T cells. Int. Immunol. 15, 49 – 59
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31 Chitnis, V. et al. (2003) Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIVgag-specific responses with exogenous IL-15. Clin. Immunol. 107, 36 – 45 32 Strengell, M. et al. (2003) IL-21 in synergy with IL-15 or IL-18 enhances IFN-g production in human NK and T cells. J. Immunol. 170, 5464– 5469 33 Bayard-McNeeley, M. et al. (1996) Differential effects of interleukin12, interleukin-15, and interleukin-2 on human immunodeficiency virus type 1 replication in vitro. Clin. Diagn. Lab. Immunol. 3, 547– 553 34 Al-Harthy, L. et al. (1998) Induction of HIV-1 replication by type 1-like cytokines, interleukin (IL)-12 and IL-15: effect on viral transcriptional activation, cellular proliferation, and endogenous cytokine production. J. Clin. Immunol. 18, 124 – 131 35 Sin, J.I. et al. (1999) IL-12 gene as a DNA vaccine adjuvant in a herpes mouse model: IL-12 enhances Th1-type CD4þ T cell-mediated protective immunity against herpes simplex virus-2 challenge. J. Immunol. 162, 2912– 2921 36 Murali-Krishna, K. et al. (1998) Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177 – 187 37 Gasser, S. et al. (2000) Constitutive expression of a chimeric receptor that delivers IL-2/IL-15 signals allows antigen-independent proliferation of CD8 þ CD44high but not other T cells. J. Immunol. 164, 5659– 5667 38 Fehniger, T.A. et al. (2002) Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev. 13, 169– 183 39 Ruchatz, H. et al. (1998) Soluble IL-15 receptor a-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J. Immunol. 160, 5654– 5660 40 Fehniger, T.A. et al. (2000) Cutting edge: IL-15 costimulates the generalized Shwartzman reaction and innate immune IFN-g production in vivo. J. Immunol. 164, 1643– 1647 41 Fehniger, T.A. et al. (2001) Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8þ T cells. J. Exp. Med. 193, 219 – 231 42 Emery, S. et al. (2000) Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease. J. Infect. Dis. 182, 428 – 434 43 Markowitz, N. et al. (2003) Nadir CD4þ T cell count predicts response to subcutaneous recombinant interleukin-2. Clin. Infect. Dis. 37, e115– e120 44 Brenchley, J.M. et al. (2003) Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8þ T cells. Blood 101, 2711 – 2720 45 Lieberman, J. et al. (2001) Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98, 1667 – 1677 46 Klenerman, P. et al. (2002) HIV: current opinion in escapology. Curr. Opin. Microbiol. 5, 408 – 413 47 Pierson, T. et al. (2000) Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu. Rev. Immunol. 18, 665 – 708 48 Appay, V. and Rowland-Jones, S.L. (2002) Premature ageing of the immune system: the cause of AIDS? Trends Immunol. 23, 580 – 585 49 van Baarle, D. et al. (2002) Failing immune control as a result of impaired CD8þ T-cell maturation: CD27 might provide a clue. Trends Immunol. 23, 586 – 591 50 van Baarle, D. et al. (2002) Lack of Epstein – Barr virus (EBV)- and HIV-specific CD272CD8þ T cells is associated with progression to viral disease in HIV-infection. AIDS 16, 2001– 2011
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Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy? Claudio M. Mastroianni, Gabriella d’Ettorre, Gabriele Forcina and Vincenzo Vullo Department of Infectious and Tropical Diseases, La Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy
The current antiretroviral therapy has improved the clinical outcome of HIV-infected patients. However, the drug toxicity, the emergence of drug-resistant HIV variants and the incomplete reconstitution of immune responses underline the need for additional therapeutic strategies, such as cytokine-based therapy. Interleukin15 (IL-15) has a central role in the immune response during HIV infection. Recently, defective production of IL-15 has been found in AIDS patients and it might account for the impairment of natural and adaptive immune responses against HIV. IL-15 is more potent than IL-2 and IL-7 in enhancing the function of HIVspecific CD81 T cells and it is a superior HIV vaccine molecular adjuvant. In this Opinion, we propose that IL-15 could be used for clinical intervention in HIV infection. The introduction of highly active antiretroviral treatment (HAART) has produced substantial clinical benefits to individuals with HIV infection, reducing opportunistic infections, rate of hospitalizations and HIV-associated mortality [1,2]. However, the major limitation of current antiretroviral therapies is the inability to eradicate the virus and to induce a full restoration of immunity against HIV [3,4]. Recently, immunological therapeutic strategies, such as cytokine-based treatment, have been proposed to augment either innate or acquired immune responses in patients with HIV infection [5– 7]. Interleukin-15 (IL-15) is a member of the common g-chain family of cytokines, also including IL-2, IL-4, IL-7, IL-9 and IL-21. It uses the b-subunit of the IL-2-receptor (IL-2R) and its own unique a-chain (IL-15Ra) as crucial signaling components. Unlike IL-2, IL-15 mRNA is present in monocytes, macrophages, dendritic cells (DCs) and many non-lymphoid tissues. IL-15 is produced by antigen-presenting cells (APCs) in the early phase of the immune response to infection and it has an important role in the regulation of innate and adaptive immune-cell functions [8] (Box 1). There are several lines of evidence documenting the increased biological relevance of IL-15 during the course of HIV infection [9]. In particular, the altered production of IL-15 might contribute to the progressive impairment of innate and adaptive immune responses that are only partially restored by antiretroviral therapy [10]. Because of its anti-apoptotic properties and its fundamental role in enhancing survival and function of
natural killer (NK) effector cells and CD8þ T cells, IL-15 has been proposed as immunorestorative agent to boost immunity against HIV [10,11]. In addition, given the ability to maintain the memory CD8þ T-cell compartment, IL-15 could also be useful as molecular vaccine adjuvant [12]. The aim of this Opinion is to highlight recent data about the central role of IL-15 in the immune response during HIV infection and its potential use as an immunotherapeutic agent. IL-15 production during HIV infection The damage to normal cytokine signaling and function is a key factor in the immunopathogenesis of HIV infection [13]. The perturbation of the cytokine network contributes both to the impairment of HIV-specific immune responses and to the increased susceptibility to opportunistic infections. Type 1 cytokines, generally, are decreased with the progression of HIV disease, whereas type 2 cytokines are increased. However, some authors have shown that there are no detectable shifts from Th1 to Th2 cytokine production in HIV infection [14,15]. Little is known in the literature about IL-15 production in HIVinfected individuals. One study indicates that circulating levels of IL-15 were elevated during HIV infection [16]. Conversely, in another investigation the amount of IL-15 secreted by peripheral blood mononuclear cells (PBMCs) Box 1. Important immunological properties of IL-15 † Interleukin-15 (IL-15) has an essential role in natural killer (NK)-cell development, differentiation and maturation. IL-15 activates NK-cell proliferation, cytotoxicity and cytokine and chemokine secretion. † IL-15 is important in the in vitro activation of the functional properties of neutrophils, by delaying apoptosis and enhancing chemotaxis and fungicidal activity. † Monocytes, macrophages and dendritic cells are a major source of IL-15 production. IL-15 exerts autocrine activity on monocytes by inducing IL-8 and monocyte chemoattractant protein-1 (MCP-1) secretion. † IL-15 induces cell proliferation and polyclonal antibody secretion in B cells. † IL-15 is a potent growth factor for T cells, promoting activation and proliferation. IL-15 stimulates human Th1-cell differentiation and acts as a potent chemoattractant for T lymphocytes, regulating T-cell trafficking in vivo. † IL-15 inhibits in vitro T-cell apoptosis and in vivo anti-Fas-induced apoptosis. † IL-15 enhances the survival, activation, interferon-g (IFN-g) production and cytotoxicity of CD8þ T cells and has an important role in regulating CD8þ T-cell homeostasis in vivo.
Corresponding author: Claudio M. Mastroianni ([email protected]). www.sciencedirect.com 1471-4906/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2004.01.002
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from HIV-infected individuals on stimulation with bacterial strains was reduced if compared with HIV-seronegative donors [17]. In a recent study, Ahmad et al. extensively evaluated the production of IL-15 in HIVinfected patients by assessing the circulating levels of cytokine as well as the ability of PBMCs to release IL-15 in response to stimulation by herpes simplex virus-1 (HSV-1) [10]. In HIV-infected patients, serum levels of IL-15 were significantly decreased compared to healthy controls. In addition, there was an impairment in IL-15 production by PBMCs on stimulation with HSV-1, especially in the advanced stage of the disease. These data are in agreement with our previous results about the production of IL-15 by stimulated PBMCs from various groups of HIV-infected patients, including those receiving antiretroviral drugs [18]. PBMCs from antiretroviral-naı¨ve patients with low CD4þ T-cell counts and patients with treatment failure were defective in their ability to release IL-15 in response to opportunistic pathogens. However, patients with a sustained increase in CD4þ count after antiretroviral therapy showed an enhanced production of IL-15. Similarly, high plasma levels of IL-15 were found in chronically HIV-infected patients, controlling viral replication after structured treatment interruption [19]. A defective production of IL-15 has been also found in a murine model of AIDS and it might account for the high susceptibility of these mice to mycobacterial infections [20]. Mice genetically deficient in IL-15 displayed a marked reduction in NK- and CD8 T-cell function, suggesting a crucial role for this cytokine in the generation of both innate and acquired effector arms of immunity [21]. Taken together, these data suggest that HIVþ PBMCs are compromised in their ability to release IL-15 in response to viral, bacterial or fungal stimuli. This deficit could lead to the damage of natural as well as adaptive immune responses during HIV infection.
…the altered production of IL-15 might contribute to the progressive impairment of innate and adaptive immune responses [during the course of HIV infection]… The production of IL-15 is impaired only at posttranscriptional level because PBMCs from HIV-infected patients constitutively express increased levels of the IL-15 gene. Increased expression of IL-15 mRNA was also found in tissues during primary simian immunodeficiency virus (SIV) infection [22]. In addition, elevated levels of mRNA for IL-15Ra were also observed in PBMCs during primary HIV infection (PHI) [23]. In such a context, IL-15 seems to be involved in the generation of proliferating CCR5þ T cells, by inhibiting spontaneous apoptosis in association with upregulation of Bcl-2 expression. The IL-15 effect on CCR5þ T cells during PHI seems to be crucial for productive HIV infection and the establishment of latently infected cells. www.sciencedirect.com
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Several cell types other than PBMCs might be involved in the dysregulated production IL-15 during HIV infection. DCs are functionally relevant sources of IL-15 in the context of immune responses and are potent APCs that are capable of activating and expanding both effector CD8þ T cells and helper CD4þ T cells [24,25]. Alterations in DC number and function could be an essential factor in the development of T-cell functional impairment in HIV infection [26]. HIV-infected DCs can exhibit changes in immunoregulatory cytokines that modulate T-cell responses and the expression of T-cell stimulatory and co-stimulatory molecules. Future studies are needed to investigate the production of IL-15 by HIV-infected DCs and the role of DC-derived IL-15 in driving the outcome of HIV-specific T-cell responses. IL-15 as an immunotherapeutic agent in HIV infection The ability of IL-15 to modulate innate and specific immune responses against HIV supports the clinical interest in using this cytokine as an immunorestorative agent during HIV infection (Figure 1). HIV-specific CD8þ T-cell responses have a central role in controlling HIV infection and disease progression. Recent data indicate that NK cells are able to control HIV replication to the same extent as CD8þ T cells [27]. In HIV-infected individuals, in vitro treatment with IL-15 improves neutrophil functional activities, increases survival and functions of NK cells and promotes the expansion of HIV specific T lymphocytes [9,28,29]. IL-15 is important in the maintenance of the memory pool of CD8þ T cells and it is efficient in enhancing survival and effector functions of HIV-specific CD8þ T cells [11,30]. Indeed, this cytokine has a potent inhibitor effect on spontaneous and CD95 (Fas)induced apoptosis of effector memory HIV-specific CD8þ cells. The mechanism of inhibition is unknown and it probably involves upregulation of intracellular level of Bcl-2 [23]. IL-15 also improves the long-term survival and effector functions of HIV-specific CD8þ T cells by increasing ex vivo cytotoxicity and interferon-g (IFN-g) production [11]. A comparative evaluation in HIV-infected pediatric patients of CD8þ T-cell responses, after in vitro treatment with IL-2, IL-7 and IL-15, showed that IL-15 is the most potent cytokine in augmenting HIV-gag-specific CD8þ T-cell responses. These findings suggest the importance of IL-15 in boosting HIV-specific immunity [31]. IFN-g is a key cytokine involved in the regulation of innate immunity and adaptive CD4þ Th1 immune responses. Therefore, the identification of cytokines that contribute to the production of IFN-g during the early stages of viral infection is an issue of great importance. IL-15, in synergy with IL-21, seems to be a potent upregulator of IFN-g gene expression in human NK and T cells by activating the Janus kinase–STAT (signal transducer and activator of transcription) pathway [32]. During HIV infection, IL-15 could have an important role in the immune restoration by maintaining and/or augmenting IFN-g production from NK cells and HIV-specific CD8þ T cells. One of the problems in using cytokines in vivo as immunotherapeutic agents for the management of HIV infection is the potential activation of HIV replication.
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Figure 1. Central role of interleukin-15 (IL-15) in the immune response during HIV infection. In response to antigens, dendritic cells (DCs) and other antigen-presenting cells (APCs), such as macrophages, produce IL-15, which stimulates interferon-g (IFN-g) production in natural killer (NK) cells and T lymphocytes. IL-15 induces Th1 T-cell differentiation, shifting the subsequent adaptive T-cell response toward Th1. In addition, IL-15 has a key role as activator of NK activity and the cytotoxic T-lymphocyte (CTL) response. HIV infection inhibits IL-15 production, decreasing the Th1 response and NK and CTL activity. IL-15 might be useful as immunotherapeutic agent to augment NK and CTL activity and to restore cell-mediated immune responses against HIV. Abbreviations: ThP, T helper precursor.
Therefore, the possible clinical use of IL-15 requires careful evaluation of the effect on HIV replication [33,34]. Data from different laboratories indicate that IL-15 has an additional advantage over other cytokines, such as IL-2, because it seems not to induce HIV replication in vitro [17,18].
…clinical use of IL-15 requires careful evaluation of the effect on HIV replication. Recent investigations suggest that Th1 cytokines could be proposed as vaccine molecular adjuvants. IL-12 can be useful as a DNA vaccine adjuvant in a herpes mouse model [35]. A recent study compared the usefulness of IL-2 and IL-15 as HIV vaccine components for inducing both longlasting cellular and humoral immune responses [12]. Coadministration of HIV vaccine vectors with vaccinia viruses (VVs) expressing IL-15 induced long-lasting cellular immunity and the T-cell mediated immunity evoked by IL-2 as vaccine adjuvants was short-lived. www.sciencedirect.com
This effect is mainly a result of the fact that IL-15 is implicated as a central player in CD8 memory T-cell homeostasis. In this regard, the administration of the VVs expressing IL-15 induces an increased number of memory CD8þ T cells expressing IL-15Ra and CD8þ T cells persist for several months showing a high proliferative response to IL-15 in vivo and in vitro. These findings, in agreement with previous studies, indicate that IL-15 can maintain memory CD8þ T-cell proliferation in an antigen-independent manner [36,37]. The potential toxicity and adverse effects of IL-15 must be kept in mind when considering administration of such a cytokine to humans [9,38]. The known properties of IL-15 as a potent antigen-independent stimulator might account for the development of direct inflammatory side effects. Because IL-15 promotes T-cell chemotaxis, adhesion molecule expression and chemokine production, it is conceivable that this cytokine could be involved in the development of antigen-induced immunopathology [39]. Studies on SCID (severe combined immunodeficiency) mice indicate that in vivo neutralization of IL-15 before the lipopolysaccharide (LPS) priming phase significantly reduces lethality in the generalized Shwartzman reaction [40]. In addition, leukemia, like other cancers, can be a
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result of chronic stimulation by proinflammatory cytokines. In particular, IL-15 transgenic mice that overexpress IL-15 show early expansion in NK and CD8þ Tcells and later develop fatal lymphocytic leukemia [41]. Given the potential toxicity of IL-15, the use of this cytokine in humans requires careful monitoring of such side-effects.
…IL-15 can maintain memory CD81 T-cell proliferation in an antigenindependent manner. A crucial issue is the identification of useful surrogate markers to assess the clinical efficacy of IL-15 in HIV infection. HIV-infected patients receiving recombinant IL-2, a cytokine with similar properties to IL-15, frequently exhibit a significant elevation in their absolute CD4þ T-cell count; however, the clinical benefit of such an increase is not yet established [42]. In a recently published study, the nadir CD4þ cell count emerged as a significant predictor of clinical response to intermittent subcutaneous administration of IL-2 [43]. Based on these findings, we believe that only future clinical trials will provide useful information to identify surrogate markers assessing the beneficial effects of IL-15 therapy in HIV infection. Another point to clarify is the stage of infection when IL-15 should be used. In our opinion, we believe that IL-15 should be administered early during the course of HIV infection when T cells maintain their ability to respond to such a cytokine. In the advanced stage of the disease, HIVspecific CD8þ T cells could reach replicative senescence or clonal exhaustion as the result of chronic immune activation. In such a context, HIV-specific CD8þ T cells might have a reduced proliferative capacity to respond to antigens even after exogenous administration of IL-15 [44]. IL-15 and immune control of HIV infection Although several studies suggest that the immune system has an important role in the response against HIV, the virus persists in the host, leading to disease progression and the development of AIDS. The reasons for a lack of effective immune control are still not completely understood. Several factors, including immune exhaustion, replicative senescence of CD8þ T cells, lack of adequate Th-cell function, immune escape, ineffective cytotoxic T-lymphocyte (CTL) responses in vivo and viral reservoirs, must be taken into consideration in explaining this phenomenon [44 –47]. It has been argued by some authors that HIV infection could lead to an acceleration of the senescence or decay of the immune system, resulting in immune exhaustion and the development of AIDS [48]. In such a context, the use of IL-15 or other cytokines as immunorestorative agents could be potentially harmful, considering the effect on T-cell expansion and differentiation. IL-15 might contribute to the overactivation and exhaustion of CD8þ T cells, leading to premature ageing of the immune system. Recent lines of evidence suggest that the reason for failing immune control of HIV infection could be ascribed www.sciencedirect.com
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to the impaired maturation of CD8þ T cells [49]. In particular, during the progression to AIDS, HIV-specific T cells do not fully differentiate to the CD272 effector stage. However, in HIV-infected long-term non progressors, T cells have a CD272 phenotype with strong direct cytolytic capacity related to the high expression of effector molecules, such as granzymes and perforin [50]. Factors that influence the HIV-specific CD8þ T-cell differentiation are not fully elucidated. IL-15, which is essential for the expansion and maintenance of CTLs, could play an important role during HIV infection. On this basis, the use of IL-15 therapy could be beneficial for the full maturation of effective HIV-specific CD8þ T cells, thus driving the immune control of infections. Concluding remarks The defective production of IL-15 in HIV-infected individuals might contribute to the impairment of NK and CD8þ T-cell function. In vitro administration of IL-15 inhibits CD95 (Fas)-induced apoptosis and enhances the survival and function of HIV-specific CD8þ T cells, indicating the importance of this cytokine in the restoration of HIVspecific immunity. In addition, IL-15 seems to be more potent than IL-2 and IL-7 in augmenting CD8þ T-cell responses. Because of its long-lasting effect on cellular immunity, IL-15 might represent an optimal cytokine adjuvant for an effective vaccine against HIV. However, the potent ability of IL-15 to induce survival and proliferation of T cells should be assessed against the possible detrimental effect of increased immune activation and accelerated immunesenescence. In addition, the use of IL-15 in humans requires careful monitoring for possible inflammatory side effects. The development of immune-based strategies for the treatment of HIV infection remains a great challenge. We propose that IL-15, through its ability to stimulate both innate and adaptive immune responses, could be used as an immunotherapeutic agent in HIV disease. Therefore, studies examining the safety and efficacy of IL-15 in animal models of HIV infection, such as SIV infection, should be strongly encouraged. References 1 Van Sighem, A.I. et al. (2003) Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS 17, 2227 – 2236 2 Mocroft, A. et al. (2003) Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 362, 22 – 29 3 Carcelain, G. et al. (2001) Reconstitution of CD4þ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr. Opin. Immunol. 13, 483 – 488 4 Valdez, H. (2002) Immune restoration after treatment of HIV-1 infection with highly active antiretroviral therapy (HAART). AIDS Rev. 4, 157 – 164 5 Autran, B. (2002) Strategies toward restoration of immunity to HIV. AIDS 16, 4 – 6 6 Letvin, N.L. and Walker, B. (2003) Immunopathogenesis and immunotherapy in AIDS virus infections. Nat. Med. 9, 861 – 866 7 Pett, S.L. and Kelleher, A.D. (2003) Cytokine therapies in HIV-1 infection: present and future. Expert Rev. Anti-Infect. Ther. 1, 83 – 96 8 Lodolce, J.P. et al. (2002) Regulation of lymphoid homeostasis by interleukin-15. Cytokine Growth Factor Rev. 13, 429 – 439 9 Fehniger, T.A. and Caligiuri, M.A. (2001) Interleukin 15: biology and relevance to human disease. Blood 97, 14– 32
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