Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?

doi:10.1016/j.it.2004.01.002

Trends in Immunology

Volume 25, Issue 3, March 2004, Pages 121-125

https://doi.org/10.1016/j.it.2004.01.002 Get rights and content

Abstract

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. Interleukin-15 (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 HIV-specific CD8⁺ 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.

Section snippets

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

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 CD8⁺ 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 CD8⁺ T cells [27]. In HIV-infected individuals, in vitro treatment with IL-15 improves neutrophil

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 CD8⁺ T cells, lack of adequate Th-cell function, immune escape, ineffective cytotoxic T-lymphocyte (CTL) responses in vivo and viral

Concluding remarks

The defective production of IL-15 in HIV-infected individuals might contribute to the impairment of NK and CD8⁺ T-cell function. In vitro administration of IL-15 inhibits CD95 (Fas)-induced apoptosis and enhances the survival and function of HIV-specific CD8⁺ T cells, indicating the importance of this cytokine in the restoration of HIV-specific immunity. In addition, IL-15 seems to be more potent than IL-2 and IL-7 in augmenting CD8⁺ T-cell responses. Because of its long-lasting effect on

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Interleukin 15 (IL-15) is an important cytokine of fish immune system. Sequence characterization of IL-15 from rohu, Labeo rohita revealed a mRNA sequence of 1064 bp with coding sequence of 567 bp and signal peptide of 16 amino acids. There are four characteristic sequence features viz., presence of four out-of-frame AUG initiation codons, four highly conserved cysteine residues, constitutive expression in all tissues and evolutionary similarity. The ontogeny study revealed maternal transfer of this molecule and higher expression up to 3 h post-fertilization in fertilized embryos. Its expression was down-regulated in anterior and posterior kidneys, intestine and liver tissues of rohu infected with Aeromonas hydrophila. Mild up-regulation in liver and higher expression in spleen was noticed in rohu stimulated with poly I:C (poly ionosinic:cytidylic), whereas down-regulation was observed in intestine and kidney tissues. However, a consistent higher expression was noticed in kidney and skin tissues during Argulus siamensis infection. Therefore, rohu IL-15 might possess more defensive role during early development and parasitic infection.
Natural killer cells and human immunodeficiency virus
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HIV-1 viraemia significantly impairs natural killer (NK) cell antiviral functions. Starting from acute infection, there is a pathologic redistribution of circulating NK cell subset that severely affects the ability of NK cells to eliminate HIV-1 infected cells. High frequencies of pathologic CD56neg/CD16pos NK cell subsets are associated with defective NK–DC interactions resulting in impaired activation and proliferation of NK cells, and deficient NK cell-mediated cytotoxicity and secretion of antiviral cytokines. Control of HIV-1 viraemia by antiretroviral therapy (ART) normalizes these parameters. TLR9 ligands may stimulate NK cells through pDC secretion of interferon (IFN)-α. Cohorts of exposed, uninfected individuals and genetic studies show protective associations between some NK inhibitory receptors and their HLA class I molecule ligands. These data offer new molecular targets for HIV-1 control through restoration of NK cell functions. Natural killer (NK) cells are a subset of lymphoid cells that function as important mediators of innate immune defence against viruses and tumor cells. Understanding the biology of NK cells, particularly the identification of novel receptors and their ligands, has enhanced our knowledge on the potential role of NK cells in the immunopathogenesis of HIV infection. However, it is still unclear whether NK cells actually control HIV replication in vivo. Previous studies have attempted to evaluate the role of NK cells in the pathogenesis of several diseases or in the control of invading pathogens in nonhuman primates. The lack of specific markers that identify the entire simian NK cell population have significantly limited the understanding of the role of this population in disease states for which only nonhuman primates offer an appropriate animal model.
Natural killer cells and human immunodeficiency virus
2009, Natural Killer Cells: Basic Science and Clinical Application
HIV-1 viraemia significantly impairs natural killer (NK) cell antiviral functions. Starting from acute infection, there is a pathologic redistribution of circulating NK cell subset that severely affects the ability of NK cells to eliminate HIV-1 infected cells. High frequencies of pathologic CD56neg/CD16pos NK cell subsets are associated with defective NK–DC interactions resulting in impaired activation and proliferation of NK cells, and deficient NK cell-mediated cytotoxicity and secretion of antiviral cytokines. Control of HIV-1 viraemia by antiretroviral therapy (ART) normalizes these parameters. TLR9 ligands may stimulate NK cells through pDC secretion of interferon (IFN)-α. Cohorts of exposed, uninfected individuals and genetic studies show protective associations between some NK inhibitory receptors and their HLA class I molecule ligands. These data offer new molecular targets for HIV-1 control through restoration of NK cell functions. Natural killer (NK) cells are a subset of lymphoid cells that function as important mediators of innate immune defence against viruses and tumor cells. Understanding the biology of NK cells, particularly the identification of novel receptors and their ligands, has enhanced our knowledge on the potential role of NK cells in the immunopathogenesis of HIV infection. However, it is still unclear whether NK cells actually control HIV replication in vivo. Previous studies have attempted to evaluate the role of NK cells in the pathogenesis of several diseases or in the control of invading pathogens in nonhuman primates. The lack of specific markers that identify the entire simian NK cell population have significantly limited the understanding of the role of this population in disease states for which only nonhuman primates offer an appropriate animal model.
Inhibitory effect of dietary n-3 polyunsaturated fatty acids to intestinal IL-15 expression is associated with reduction of TCRαβ+CD8α+CD8β- intestinal intraepithelial lymphocytes
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Intestinal intraepithelial lymphocytes (IELs) and their cytokines play an important role in the regulation of gut immune response and take part in gut immune barrier function. n-3 polyunsaturated fatty acid (PUFA) is an immunoregulator that has been shown to influence the process of gut inflammation. Interleukin (IL)-15 is a T-cell growth factor that has been shown to influence the differentiation of IEL. The aim of this study was to analyze the effects of dietary n-3 PUFA on IEL. IEL phenotype and cytokine (TNF-α, IFN-γ, IL-4, IL-10 and TGF-β1) profile were measured by FACS and real-time RT-PCR in healthy adult rats fed with fish oil diet for 90 days. Rats fed with corn oil diet served as controls. Intestinal IL-15 expression was measured by immunohistochemistry and real-time RT-PCR. The results demonstrated a decrease of intestinal IL-15 expression in the fish oil group. Associated with this deduction, n-3 PUFA significantly decreased the proportion of TCRαβ+CD8α+CD8β− cells and IEL-derived TNF-α, IFN-γ, IL-4 and IL-10. In conclusion, n-3 PUFA could inhibit intestinal mucosal expression of IL-15 and may influence phenotype and function of IEL through this mechanism.
Efficient augmentation of a long-lasting immune responses in HIV-1 gag DNA vaccination by IL-15 plasmid boosting
2008, Vaccine
Citation Excerpt :
Cytokines and chemokines are believed to enhance vaccine-induced immune responses by the recruitment of professional antigen presenting cells (APC), the activation of antigen specific T and B cells and the migration of the memory lymphocyte when infection occurs [7,10]. Interleukin (IL)-15 belongs to the gamma chain family of cytokines, which includes IL-2, IL-4, IL-7, IL-9 and IL-21 [11]. IL-15 is expressed at the mRNA level in many normal tissues and produced by APC in the early phase of an immune response.
Cytokines are major regulators of the immune response, and have been used as adjuvants to improve vaccine potency. In this study, we investigated the adjuvant effects of interleukin (IL)-15 on improving the immunogenicity of human immunodeficiency virus (HIV)-1 gag DNA vaccine in Balb/c mice. During a 370-day follow-up, cellular and humoral immune responses in three separate cohorts of mice were monitored. These results were exemplified through: lymphocyte proliferation, induction of antigen-specific CD8⁺ T lymphocytes, long-term production of specific antibodies, and proportion of differentiated memory CD8⁺ T cells. These data revealed that just boost of IL-15 at day 8 after co-immunization induced more homeostatic cell proliferation, augmented proliferation frequency of IFN-γ-secreting antigen-specific CD8⁺ T lymphocytes, maintained the long-lasting humoral immune response and promoted the turnover of memory T cell precursors into central memory T cells. Taken together, our data demonstrated that a single IL-15 boosting can enhance both the humoral and cellular immune responses of the HIV-1 gag DNA vaccination. This novel boosting strategy may facilitate the application of IL-15 as an adjuvant for HIV vaccination.
Central role of interleukin-15 in human immunodeficiency virus (HIV)-infected patients with visceral leishmaniasis
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Recently, we have found that IL-15 enhance the in vitro priming of CD4+ and CD8+ T cells for IFN-γ and β-chemokine production in patients with HIV infection (Forcina et al., 2004.). In addition, a defective production of IL-15 has been found in AIDS patients and it might account for the impairment of immune responses against HIV (Mastroianni et al., 2004). In this study the epidemiology, clinical characteristics, immunological parameters, and outcome of 48 cases of visceral leishmaniasis (VL), including also patients with HIV infection, occurring over a 15-year period was reviewed.
To evaluate clinical and immunological parameters, interleukin (IL)-15 production and outcome of patients with visceral leishmaniasis (VL), including HIV positive patients, we analyzed 48 cases of VL.
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Our data demonstrate that VL in HIV-infected patients occurs in subjects with severe immunodeficiency and presents high rate of relapses. Low levels of IL-15 in illness patients and restored production in cured persons suggest that this cytokine could play a central role in immune responses during Leishmania/HIV co-infection.

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Trends in Immunology

Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?

Abstract

Section snippets

IL-15 production during HIV infection

IL-15 as an immunotherapeutic agent in HIV infection

IL-15 and immune control of HIV infection

Concluding remarks

Lancet

Curr. Opin. Immunol.

Cytokine Growth Factor Rev.

Blood

Blood

Microbes Infect.

Cell

Blood

Immunol. Lett.

Clin. Immunol.

Immunity

Cytokine Growth Factor Rev.

Blood

Blood

Curr. Opin. Microbiol.

Trends Immunol.

Trends Immunol.

Mortality and progression to AIDS after starting highly active antiretroviral therapy

AIDS

Immune restoration after treatment of HIV-1 infection with highly active antiretroviral therapy (HAART)

AIDS Rev.

Strategies toward restoration of immunity to HIV

AIDS

Immunopathogenesis and immunotherapy in AIDS virus infections

Nat. Med.

Cytokine therapies in HIV-1 infection: present and future

Expert Rev. Anti-Infect. Ther.

Studies on the production of IL-15 in HIV-infected/AIDS patients

J. Clin. Immunol.

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.

Host factors and pathogenesis of HIV-induced disease

Nature