Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The newly identified cytokine, IL-15 enhanced antigen-induced proliferation of PBMC obtained from HIV-1-seropositive subjects. When compared to IL-2 which enhanced both spontaneous and antigen-induced lymphocyte proliferative responses, IL-15 rarely increased spontaneous lymphocyte proliferation. Additionally, in cultures of lymphocytes obtained from 15 HIV-1-infected patients with < 300 circulating CD4- lymphocytes/microliter IL-15 induced significant HIV-1 expression (46, 21, and 71 pg/ml) in only 3 of 15 experiments and IL-2 induced significant HIV-1 expression (range 16- > 5000 pg/ml) in 11 of 15 experiments (P < 0.01, Fischer's exact test). Simultaneous assays of cytokine-induced spontaneous lymphocyte proliferation and HIV-1 expression revealed similar dose-response relationships for induction of HIV-1 and lymphocyte proliferation by IL-2. Thus, IL-15 helps to correct the impaired proliferative response of CD4+ lymphocytes from HIV-1-infected persons without the mitogenic effect of IL-2 that also may induce HIV-1 expression.
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PMID:Activation of antigen-induced lymphocyte proliferation by interleukin-15 without the mitogenic effect of interleukin-2 that may induce human immunodeficiency virus-1 expression. 869 51

It has been assumed that the maturation of pre-CTL to virus-specific effector CTL is dependent upon IL-2-mediated T cell triggering through the IL-2R. In view of its similarity to IL-2 in its effects on immune cells, we sought to determine whether IL-15 can induce the expansion of AIDS virus-specific pre-CTL to mature CTL. PBL of SIV(mac)-infected rhesus monkeys or HIV-1-infected humans have previously been shown to expand to effector CTL when cultivated with a predicted CTL epitope peptide and rIL-2. We now demonstrate that rIL-15 facilitates this expansion of effector CTL. In fact, rIL-15-driven expansion of virus-specific CTL occurs in the presence of IL-2-neutralizing or anti-IL-2R Abs, indicating that this cellular maturation can occur in an IL-2-independent fashion. These studies suggest a mechanism by which CTL may be capable of expanding in vivo in the absence of IL-2 and functional CD4+ T lymphocytes.
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PMID:IL-15 stimulates the expansion of AIDS virus-specific CTL. 887 70

Cytokines may have clinical utility as therapeutic agents for human immunodeficiency virus type 1 (HIV-1) infection and as an adjuvant for vaccines. The effect of interleukin-12 (IL-12) and IL-15 on in vitro HIV-1 replication was investigated. IL-12 and IL-15 at doses up to 10 ng/ml had little effect on basal HIV-1 p24 antigen production by chronically HIV-infected T (ACH-2) and monocytic (U1) cell lines. For ACH-2 cells stimulated with phorbol 12-myristate 13-acetate (PMA; 50 ng/ml), IL-12 and IL-15 significantly increased p24 antigen production by 20 and 30%, respectively (n = 6). In contrast, IL-12 and IL-15 (10 ng/ml) treatment of PMA-stimulated U1 cells decreased p24 antigen production by 16 and 15%, respectively (n = 6). We next studied the effect of IL-12 and IL-15 on HIV-infected peripheral blood mononuclear cells (PBMCs). In 10 HIV-seropositive patients' PBMCs cocultured with mitogen-activated HIV-seronegative donor cells, two patterns of p24 antigen production were observed in response to IL-2: low (p24 antigen production < 10(3) pg/ml; n = 8) and high (p24 antigen production > 10(3) pg/ml; n = 2) response. For the low-response pattern, IL-12 and IL-15 increased viral replication by 97-fold and 100-fold, respectively (P = 0.05 and 0.004, respectively). For the high-response pattern, both IL-12 and IL-15 suppressed HIV replication. The effect of IL-2, IL-12, and IL-15 on acute in vitro infection by HIV-1JRCSF was also examined. IL-12 did not increase p24 antigen production above basal levels while IL-2 and IL-15 significantly enhanced p24 antigen production (by approximately 2-fold). In conclusion, IL-12 and IL-15 may have differential effects on latent and acute HIV infection, and their ability to enhance HIV production may depend on cell activation. Thus, the use of these cytokines may be dictated by the clinical state of the patient.
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PMID:Differential effects of interleukin-12, interleukin-15, and interleukin-2 on human immunodeficiency virus type 1 replication in vitro. 887 33

IL-15 is a novel cytokine, produced by monocytes/macrophages, with biological activities similar to IL-2 but with no significant sequence homology. IL-15 also stimulates human B cells to proliferation and immunoglobulin secretion. We measured serum levels of IL-15 in 84 HIV-1-infected individuals at different stages of disease in reference to 41 healthy blood donors. Our results show a marked elevation of IL-15 serum levels during HIV-1 infection. Moreover, we found that this increase correlated with serum levels of IgG (r = 0.376, P < 0.0001), and partly with serum IgM (r = 0.265, P = 0.015). A significant increase of IL-15 production by cultured peripheral blood mononuclear cells (PBMC) and purified monocytes in the presence of HIV-1 virus suggests that monocytes/macrophages may be a source of higher IL-15 serum levels in HIV-1-infected individuals. These findings indicate a participation of IL-15 in the hypergammaglobulinaemia frequently associated with HIV-1 infection.
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PMID:Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. 909 5

IL-15, a new cytokine primarily produced by macrophages, has been shown to exhibit several functional properties shared with IL-2. Treatment of PBMC from HIV-infected patients with IL-15 resulted in an increase in NK cell cytotoxicity to levels similar to those of untreated PBMC from healthy donors. This effect is independent of several well-characterized regulatory cytokines, as it is not prevented by Abs that neutralize IFNs, TNF-alpha, IL-2, or IL-12. Enhanced cytotoxicity was accompanied by a significant increase in expression of cytotoxic granules. IL-15 enhanced the proliferative ability in both controls and HIV-seropositive in response to mitogen and recall Ags. Although the addition of IL-15 has a preventive effect on the appearance of spontaneous cell death, this effect was not seen during mitogen-induced apoptosis. The production of IL-15 by PBMC from patients in response to Staphylococcus aureus Cowan strain 1 appeared heterogeneous and was not negatively regulated by cytokines that inhibited IL-12 production. No correlation was found between in vitro HIV infection and IL-15 production, as viral infection had no effect on the ability of monocytes to produce IL-15 in response to S. aureus. Interestingly IL-15 restored the deficient production of IL-12 by PBMC from HIV+ people and had no major effect on modulating viral expression in latently infected cell lines or PBMC from naturally infected people. Taken together, these results suggest a potent immunoregulatory role of IL-15 during HIV infection.
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PMID:IL-15 enhances immune functions during HIV infection. 919 Sep 52

Natural killer (NK) cells are an important subset of lymphocytes capable of killing virus-infected target cells without prior sensitization. HIV-infected individuals show impairment of their NK cell activity. Although the mechanism responsible for this defect remains unclear, NK cytotoxicity of lymphocytes from these individuals can be partially restored by interleukin (IL)-2. IL-15 is a recently discovered cytokine that shares many biologic activities with IL-2--for example, enhancement of NK activity. In this study, we investigated the effect of recombinant IL-15 (rIL-15) on the NK and antibody-dependent cellular cytotoxicity (ADCC) effector activities of peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals using K562 cell line and HIV gp120-expressing cells. The effect of anti-IL-15 antibodies on NK activity was also examined using PBMCs of HIV-seronegative individuals. Our results show that NK and ADCC activities of PBMCs in HIV-seropositive patients were significantly lower than those of seronegative donors (p < or = 0.05). However, these two activities were significantly enhanced when rIL-15 was added to the assay wells (p < or = 0.05). Moreover, addition of saturating concentrations of neutralizing monoclonal antibodies (mAb) specific for IL-2, IL-12, or interferon (IFN)-gamma in the assays failed to inhibit IL-15-mediated enhancement of NK cell functions. Only the antibody against IL-15 abrogated the upregulation of NK and ADCC activities mediated by IL-15, suggesting that this cytokine enhances NK cell functions through a mechanism that is independent of the induction of other cytokines. IL-15 did not exert any modulatory effect on the expression of CD16 or CD56 molecules. Our results show that IL-15 can increase the NK and ADCC activities of the PBMCs of HIV-infected individuals in vitro. In view of its higher therapeutic index as determined using murine models, IL-15 may represent a better immunotherapeutic agent than IL-2 to restore these functions in HIV-seropositive patients.
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PMID:Enhancement of natural killer and antibody-dependent cytolytic activities of the peripheral blood mononuclear cells of HIV-infected patients by recombinant IL-15. 939 May 64

Because CD1-restricted T cells lack CD4 but produce IFN-gamma in response to nonpeptide mycobacterial antigens, they could play a unique role in immunity to tuberculosis. We studied CD1-restricted T cells in the context of HIV infection by expanding CD4(-) T cell lines from 10 HIV-infected patients. Upon stimulation with Mycobacterium tuberculosis antigen or upon exposure to macrophages infected with M. tuberculosis, these T cell lines proliferated, produced IFN-gamma, and showed cytolytic T cell (CTL) activity against macrophages pulsed with mycobacterial antigen, findings consistent with a protective role against M. tuberculosis. Anti-CD1b antibodies abrogated T cell proliferation, IFN-gamma production, and CTL activity, demonstrating that these T cells are CD1 restricted. IFN-gamma production in response to M. tuberculosis was enhanced by antitransforming growth factor-beta in 8/10 lines, and by IL-15 in 2/10 lines. IFN-gamma production was augmented in a nonantigen-specific manner by IL-12 in 4/8 lines. When live HIV was cocultured with CD1-restricted T cell lines, p24 antigen and proviral DNA were not detected, indicating that the T cells were not infectable with HIV. Vaccination strategies aimed at activation and expansion of M. tuberculosis-reactive CD1-restricted T cells in HIV-infected patients may constitute a novel means to provide protection against tuberculosis, while minimizing the risk of enhancing HIV replication through stimulation of CD4(+) cells.
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PMID:Isolation of mycobacterium-reactive CD1-restricted T cells from patients with human immunodeficiency virus infection. 943 10

Cytokine dysregulation is evident in HIV-1 infection and it may play an important role in HIV-1 pathogenesis. Administration of T helper cytokines potentially may restore the functional abnormalities to the HIV-1 immune response. Type 1-like cytokines, IL-2, IL-12, and IL-15, are candidates for immune-based therapy for HIV. Given their potential therapeutic use, we determined the effects of IL-2, IL-12, and IL-15 on HIV-1 replication in both primary blood mononuclear cells (PBMC) and the T-cell line, Kit 225-K6. We demonstrate that both IL-2 and IL-12 induce a similar level of HIV-1 replication (9- and 11-fold, respectively) in mitogen-stimulated PBMC. The effect of IL-2 plateaued by day 6, while that of IL-12 continued to increase HIV-1 expression. IL-15 induced a 2.5-fold increase in HIV-1 expression that remained at the same level through day 6. In Kit 225-K6, an IL-2-dependent T cell line, IL-12 and IL-15 enhanced HIV-1 replication by 5- and 3.5-fold over IL-2-treated cultures, respectively. IL-2-, IL-12-, and IL-15-mediated induction of HIV was independent of direct HIV-1 LTR activation, since none of the cytokines induced LTR activity from transfected reporter gene constructs. The cytokine-mediated induction of HIV-1 expression was also independent of cellular proliferation. In PBMC, the IL-12-mediated effect was partially mediated by endogenous cytokine production of IL-1beta and IL-7, whereas in Kit 225-K6, TNFalpha, INFgamma, IL-1beta, and IL-7 did not contribute significantly to the IL-12-mediated effect. IL-15 effect on HIV-1 in PBMC was independent of endogenous cytokine production. However, in Kit 225-K6, neutralizing antibodies to IL-7 had a significant effect on HIV-1 expression. These data suggest that IL-2, IL-12, and IL-15 increase HIV-1 replication predominantly through a posttranscriptional mechanism that may be enhanced by endogenous cytokine production.
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PMID: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. 953 56

Immunization with nucleic acids has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. We hypothesize that immunization with DNA could be enhanced by directing specific immune responses induced by the vaccine based on the differential correlates of protection known for a particular pathogen. Recently we and others reported that specific immune responses generated by DNA vaccine could be modulated by co-delivery of gene expression cassettes encoding for IL-12, granulocyte-macrophage colony-stimulating factor and the co-stimulatory molecule CD86. To further engineer the immune response in vivo, we investigated the induction and regulation of immune responses following the co-delivery of pro-inflammatory cytokine (IL-1 alpha, TNF-alpha, and TNF-beta), Th1 cytokine (IL-2, IL-12, IL-15, and IL-18), and Th2 cytokine (IL-4, IL-5 and IL-10) genes. We observed enhancement of antigen-specific humoral response with the co-delivery of Th2 cytokine genes IL-4, IL-5, and IL-10 as well as those of IL-2 and IL-18. A dramatic increase in antigen-specific T helper cell proliferation was seen with IL-2 and TNF-alpha gene co-injections. In addition, we observed a significant enhancement of the cytotoxic response with the co-administration of TNF-alpha and IL-15 genes with HIV-1 DNA immunogens. These increases in CTL response were both MHC class I restricted and CD8+ T cell dependent. Together with earlier reports on the utility of co-immunizing using immunologically important molecules together with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.
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PMID:Modulation of amplitude and direction of in vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens. 954 5

We investigated whether gamma delta T cells contribute to the suppression of myelopoiesis in HIV infection. Freshly isolated gamma delta T cells from HIV seropositive patients suppressed CFU-GM growth in vitro. Preactivation of gamma delta T cells with IL-2 and/or IL-15 further reduced the number of CFU-GM. Natural killer cells and to a lower extent CD4+ and CD8+ cells also inhibited CFU-GM growth. In contrast to gamma delta T cells, this effect was not dependent on IL-15 or IL-2 preactivation. Moreover, no enhanced inhibitory effect of CD56+ and CD4+ cells was observed in HIV+ subjects compared to HIV- donors. The myelosuppressive effect of supernatants of gamma delta T cells could be inhibited by antibodies against IFN-gamma or TNF-alpha. Accordingly, we found increased numbers of TNF-alpha or IFN-gamma-secreting CD8+ gamma delta T cells in HIV+ patients. We conclude that the increased fraction of activated gamma delta T cells producing myelosuppressive cytokines might contribute to the dyshematopoiesis frequently observed in HIV-infected individuals.
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PMID:Mechanism of gamma sigma T-cell-mediated inhibition of stem cell differentiation in vitro: possible relevance for myelosuppression in HIV-infected individuals. 962 32


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