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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines play an important role in controlling the homoeostasis of the immune system. Infection with HIV results in dysregulation of the cytokine profile in vivo and in vitro. During the course of HIV-1 infection secretion of T-helper type 1 (Th1) cytokines, such as interleukin (IL)-2, and antiviral interferon (IFN)-gamma, is generally decreased, whereas production of T helper type 2 (Th2) cytokines, IL-4, IL-10, proinflammatory cytokines (IL-1, IL-6, IL-8) and tumour necrosis factor (TNF)-alpha, is increased. Such abnormal cytokine production contributes to the pathogenesis of the disease by impairing cell-mediated immunity. A number of cytokines have been shown to modulate in vitro HIV-1 infection and replication in both CD4 T lymphocytes and cells of macrophage lineage. HIV-inductive cytokines include: TNF-alpha, TNF-beta, IL-1 and IL-6, which stimulate HIV-1 replication in T cells and monocyte-derived macrophages (MDM), IL-2, IL-7 and IL-15, which upregulate HIV-1 in T cells, and macrophage-colony stimulating factor, which stimulates HIV-1 in MDM. HIV-suppressive cytokines include: IFN-alpha, IFN-beta and IL-16, which inhibit HIV-1 replication in T cells and MDM, and IL-10 and IL-13, which inhibit HIV-1 in MDM. Bifunctional cytokines such as IFN-gamma, IL-4 and granulocyte-macrophage colony-stimulating factor have been shown to have both inhibitory and stimulatory effects on HIV-1. The beta-chemokines, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES are important inhibitors of macrophage-tropic strains of HIV-1, whereas the alpha-chemokine stromal-derived factor-1 suppresses infection of T-tropic strains of HIV-1. This review outlines the interactions between cytokines and HIV-1, and presents clinical applications of cytokine therapy combined with highly active antiretroviral therapy or vaccines.
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PMID:Cytokines and HIV-1: interactions and clinical implications. 1295 22

Previous studies have shown that human natural killer (NK) cells are lost from the periphery and are functionally suppressed during HIV-1 infection, and that the administration of highly active antiretroviral therapy (HAART) results in a recovery of NK cell numbers in HIV-1-infected individuals. However, despite this recovery, interleukin (IL)-2 + IL-12-driven interferon (IFN)-gamma production by NK cells has been shown to remain suppressed after HAART. Here we show that the innate immune factor IL-15 in combination with IL-12 is also unable to recover NK cell IFN-gamma production in HAART-treated individuals. Furthermore, we also demonstrate an imbalance in the distribution of CD56loCD16hi and CD56hiCD16- NK subsets after successful HAART, CD56hiCD16- cells being reduced substantially in HIV-1 patients on HAART. Treatment of patients with combined human growth hormone and antiretroviral therapy resulted in further enhancement in the absolute numbers and the proportion of NK cells in some individuals in the absence of parallel effects on CD4+ T cells. Furthermore, in these individuals HAART with growth hormone resulted in an enhancement of cytokine-driven NK cell activation and IFN-gamma production compared to the HAART-only baseline.
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PMID:Loss of the CD56hiCD16- NK cell subset and NK cell interferon-gamma production during antiretroviral therapy for HIV-1: partial recovery by human growth hormone. 1463 53

The CD8+ cell noncytotoxic anti-HIV response (CNAR) is associated with a long-term healthy clinical state in HIV-infected individuals. Over time CNAR is reduced concomitant with progression to disease. In studies to evaluate whether the interaction between CD8+ cells and dendritic cells (DCs) could increase CNAR, CD8+ cells from individuals who showed a decrease in this antiviral activity were cocultured with monocyte-derived dendritic cells matured with CD40 ligand. After coculture with these mature DCs, the CD8+ cells showed an increase in CNAR greater than that observed with CD8+ cells costimulated with CD3/CD28 antibodies. This antiviral response appeared to be mediated primarily by production of interleukin-15 (IL-15) by the mature DCs. Purified IL-15 also enhanced CNAR, whereas IL-12 showed no substantial effect. These studies provide another potential approach by which the immune system in HIV infection could be restored by cytokine therapy, particularly IL-15 administration.
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PMID:Mature dendritic cells can enhance CD8+ cell noncytotoxic anti-HIV responses: the role of IL-15. 1468 14

A discordant response to highly active antiretroviral therapy (HAART) occurs when CD4 T cell counts are stable or increased over time despite persistently detectable HIV-RNA levels. In order to identify immunological factors affecting discordant treatment responses, a total of 27 HIV-infected patients were studied: (a) 10 naive patients (mean CD4+ = 101.5 cells/microl; mean HIV-RNA = 4.8 log10 copies/ml); (b) seven responder patients (mean CD4+ = 908.9 cells/microl); and (c) 10 discordant patients (mean CD4+ = 396.1 cells/microl; mean HIV-RNA = 5.4 log10 copies/ml). Five healthy blood donors were included as HIV-seronegative controls. The following parameters were evaluated: interleukin (IL)-15 production by monocyte-derived dendritic cells (MDDC) after stimulation with lypopolysaccaride (LPS) and Candida albicans; recall and HIV-1-specific antigen lymphocyte proliferation (LP). Increased levels of IL-15 production by MDDC after stimulation with LPS and C. albicans were found both in discordant patients and responder patients. Conversely, a strong reduction of IL-15 levels was observed in naive patients. Discordant patients developed positive LP responses to C. albicans and HIV-1 p24. LP in response to C. albicans and HIV-1 p24 was also positive in responder patients. Decreased LP response was found in naive patients. In conclusion, HIV-infected patients with discordant viro-immunological responses to HAART present increased levels of IL-15 production by MDDC and enhanced recall and HIV-1-specific antigen LP responses, suggesting an improvement in indices of immune function.
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PMID:Interleukin-15 production by monocyte-derived dendritic cells and T cell proliferation in HIV-infected patients with discordant response to highly active antiretroviral therapy. 1473 57

Human immunodeficiency virus-specific CD8(+) T cells are highly sensitive to spontaneous and CD95/Fas-induced apoptosis, and this sensitivity may impair their ability to control HIV infection. To elucidate the mechanism behind this sensitivity, in this study we examined the levels of antiapoptotic molecules Bcl-2 and Bcl-x(L) in HIV-specific CD8(+) T cells from HIV-infected individuals. Bcl-2 expression was markedly decreased in HIV-specific CD8(+) T cells compared with CMV-specific and total CD8(+) T cells from HIV-infected individuals as well as total CD8(+) T cells from healthy donors. CD8(+) T cell Bcl-2 levels inversely correlated with spontaneous and CD95/Fas-induced apoptosis of CD8(+) T cells from HIV-infected individuals. HIV-specific CD8(+) T cells also had significantly lower levels of Bcl-x(L) compared with CMV-specific CD8(+) T cells. Finally, IL-15 induces both Bcl-2 and Bcl-x(L) expression in HIV-specific and total CD8(+) T cells, and this correlated with apoptosis inhibition and increased survival in both short- and long-term cultures. Our data indicate that reduced Bcl-2 and Bcl-x(L) may play an important role in the increased sensitivity to apoptosis of HIV-specific CD8(+) T cells and suggest a possible mechanism by which IL-15 increases their survival.
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PMID:HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. 1503 60

Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-2, and plays important immunoregulatory functions during HIV disease. To evaluate the role of IL-15 in HIV infection the following patients were studied: 18 antiretroviral-naive patients with advanced disease; 19 patients with continuous viral suppression and immunological response after 48-120 weeks of highly active antiretroviral therapy (HAART); and 12 patients with evidence of virological and immunological HAART treatment failure. Nineteen healthy blood donors were included as controls. The production of IL-15 by human peripheral blood monocytes stimulated with lipopolysaccharide and Mycobacterium avium complex, the priming effect of IL-15 on IFN-gamma production from purified CD4(+) and CD8(+) T cells, and the ability of IL-15 to stimulate the beta-chemokine release from purified CD4(+) and CD8(+) T cells were analyzed. In the present work IL-15 production by human peripheral blood monocytes was significantly increased in HIV-infected patients with long-term virological and immunological response to HAART. IL-15 enhanced the in vitro priming of CD4(+) and CD8(+) T cells for IFN-gamma production, also in patients receiving HAART. Finally, IL-15 had positive effects on RANTES, MIP-1alpha, and MIP-1beta release by CD4(+) and CD8(+) T cells. In conclusion IL-15 could affect the immune response of HIV-infected patients by augmenting and/or modulating IFN-gamma production and beta-chemokine release. These data about functional properties of IL-15 could provide new implications for immune-based therapies in HIV infection.
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PMID:Interleukin-15 modulates interferon-gamma and beta-chemokine production in patients with HIV infection: implications for immune-based therapy. 1503 44

The ability of interleukin-7 (IL-7) and IL-15 to expand and/or augment effector cell functions may be of therapeutic benefit to human immunodeficiency virus (HIV)-infected patients. The functional effects of these cytokines on innate HIV-specific immunity and their impact on cells harboring HIV are unknown. We demonstrate that both IL-7 and IL-15 augment natural killer (NK) function by using cells (CD3(-) CD16(+) CD56(+)) from both HIV-positive and -negative donors. Whereas IL-7 enhances NK function through upregulation of Fas ligand, the effect of IL-15 is mediated through upregulation of tumor necrosis factor-related apoptosis-inducing ligand. The difference in these effector mechanisms is reflected by the ability of IL-15-treated but not IL-7-treated NK cells to reduce the burden of replication-competent HIV in autologous peripheral blood mononuclear cells (PBMC) (infectious units per million for control NK cells, 6.79; for IL-7-treated NK cells, 236.17; for IL-15-treated cells, 1.01; P = 0.01 versus control). In addition, the treatment of PBMC with IL-15-treated but not IL-7-treated NK cells causes undetectable HIV p24 (five of five cases), HIV RNA (five of five cases), or HIV DNA (three of five cases). These results support the concept of adjuvant immunotherapy of HIV infection with either IL-7 or IL-15 but suggest that the NK-mediated antiviral effect of IL-15 may be superior.
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PMID:Differential effects of interleukin-7 and interleukin-15 on NK cell anti-human immunodeficiency virus activity. 1514 Oct 1

The ability to study HIV-1-specific cytotoxic T cell (CTL) clones in models in vitro or to expand them for immunotherapeutic use is limited by the technical difficulty of propagating these cells. The factors that determine the survival and proliferation of the cells are incompletely understood and could include cytokines provided from feeder cells or serum. We therefore investigated the effects of adding two cytokines reported to have effects on T cell proliferation and function, interleukin (IL)-7 and IL-15. Four HIV-1-specific clones derived from infected persons were cultured under standard conditions with IL-2 compared to IL-7 or IL-15 alone or in combination with IL-2. Proliferation and survival, as reflected by cell numbers after stimulation, were poorly supported by IL-7 or IL-15 alone, and these cytokines appeared to provide no additional benefit when added to IL-2. Similarly, these cytokines alone did not support the functional status of these cells as measured by chromium release assays with peptide-pulsed target cells. Addition of IL-7 or IL-15 to IL-2 did not augment function of the cells. These data suggest that supplementing CTL cultures with these cytokines does not provide improvement of cell growth or function.
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PMID:Culturing of HIV-1-specific cytotoxic T lymphocytes with interleukin-7 and interleukin-15. 1524 57

Correlates of immune reconstitution after highly active antiretroviral therapy (HAART) are not completely understood, in particular as far as viro-immunological discordant responses are concerned. HIV-positive patients on stable HAART for > or = 1 year were recruited. Viro-immunological responses were categorized according to positive or negative area under the curve (AUC) variations for HIV plasma viral load (pVL) and CD4+ T-cell counts measured at least every 4 months. The following parameters were evaluated: lymphocyte spontaneous apoptosis (LSA), intracellular Bcl-2 expression in both CD4-CD45RA+ and CD4-CD45R0+, IL-7 and IL-15 plasma concentrations, and lymphocyte TRECs levels. Sixty-one patients were enrolled. A significant inverse correlation was found between CD4+ T-cell count and pVL AUC (r = 0.45; p = 0.0003). Patients with pVL response had higher levels of Bcl-2 in CD4-CD45R0+ (mean 65,409 MESF vs. 54,018 MESF; p = 0.089) and higher IL-15 (mean 1.34 pg/mL vs. 1.05 pg/mL; p = 0.069, respectively). Higher LSA and lower TRECs levels were found in viro-immunological non-responder patients with respect to those who had viro-immunological response (mean 24.84% vs. 14.89%; p = 0.01, and mean 17,796 copies/10(6) cells vs. 29,251 copies/10(6) cells; p = 0.68, respectively). Virological suppression may allow Bcl-2 and IL-15 hyperexpression during incomplete immune-reconstitution phase, while more complete immune reconstitution appeared to be marked by both high TRECs and low LSA levels, possibly indicating both central and peripheral CD4+ T-cell repopulations at this stage.
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PMID:Immune correlates of virological response in HIV-positive patients after highly active antiretroviral therapy (HAART). 1527 5

BACKGROUND: A vaccine that elicits durable, powerful anti-HIV immunity remains an elusive goal. In these studies we tested whether multiple treatments with viral vector-delivered HIV envelope antigen (gp120), with and without IL-15, could help to approach that goal. For this purpose, we used recombinant Tag-deleted SV40-derived vectors (rSV40s), since they do not elicit neutralizing antibody responses, and so can be given multiply without loss of transduction efficiency. METHODS: SV(gp120) carried the coding sequences for HIV-1NL4-3 Env, and SV(mIL-15) carried the cDNA for mouse IL-15. Singly, and in combination, these two vectors were given monthly to BALB/cJ mice. Cytotoxic immunity and cytotoxic memory were tested in direct cytotoxicity assays using unselected effector cells. Antibody vs. gp120 was measured in a binding assay. In both cases, targets were P815 cells that were stably transfected with gp120. RESULTS: Multiple injections of SV(gp120) elicited powerful anti-gp120 cytolytic activity (>70% specific lysis) by unselected spleen cells. Cells from multiply-immunized mice that were rested 1 year after their last injections still showed >60% gp120-specific lysis. Anti-gp120 antibody was first detected after 2 monthly injections of SV(gp120) and remained elevated thereafter. Adding SV(mIL-15) to the immunization regimen dramatically accelerated the development of memory cytolytic responses, with >/= 50% specific lysis seen 1 month after two treatments. IL-15 did not alter the development of antibody responses. CONCLUSIONS: Thus, rSV40s encoding antigens and immunostimulatory cytokines may be useful tools for priming and/or boosting immune responses against HIV.
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PMID:Durable cytotoxic immune responses against gp120 elicited by recombinant SV40 vectors encoding HIV-1 gp120 +/- IL-15. 1532 56


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