Interleukin-15 production by monocyte-derived dendritic cells and T cell proliferation in HIV-infected patients with discordant response to highly active antiretroviral therapy (original) (raw)
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AIDS, 2002
Objective: To investigate the immunological and virological interactions between interleukin (IL)-15 and HIV in antiretroviral-naive and highly active antiretroviral therapy (HAART)-treated patients. Design: Three groups of HIV-infected patients were studied: 20 untreated patients with advanced disease; eight patients with viral suppression and immunological response to HAART; and 10 patients with virological and immunological treatment failure. Eleven healthy blood donors were included as controls. Methods: The following parameters were evaluated: the production of IL-15 by peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide, Candida albicans and Mycobacterium avium complex; the ability of IL-15 to induce the secretion of IL-8 and monocyte chemotactic protein-1 (MCP-1) from HIV-positive monocytes; and the virological effect of IL-15 and IL-2 on HIV replication in mononuclear cells. Results: IL-15 production by PBMC was signi®cantly decreased in antiretroviral-naive patients and in those with treatment failure. On the contrary, in patients with response to HAART IL-15 production was comparable to that of healthy donors. IL-15 was able to stimulate HIV-positive monocytes to produce chemokines, such as IL-8 and MCP-1, that speci®cally attract neutrophils and monocytes to the site of in¯ammation thus possibly improving immune response to pathogens during HIV infection. Finally, IL-15 had no major effect on HIV replication in vitro, while only simultaneous administration with IL-2 may induce high levels of HIV production. Conclusions: This in vitro study provides new insights in the area of IL-15±HIV interactions and suggests that IL-15 may represent a potential candidate for cytokine treatment in combination with HAART during HIV infection.
Studies on the production of IL-15 in HIV-infected/AIDS patients
Journal of clinical immunology, 2003
IL-15 is essential for the development and differentiation of NK cells. It selectively induces proliferation of CD8+ memory T lymphocytes. Despite its importance in both innate and adaptive immune responses, little is known about its production in HIV-infected persons. We report here that IL-15 levels are significantly decreased in the sera of HIV-infected/AIDS patients compared to control sera. We also show that PBMC from the infected patients are compromised in their ability to respond with enhanced production of IL-15 upon exposure to HSV-1. The decreased production of IL-15 occurs despite a comparable increase in IL-15 mRNA in the PBMC of HIV-infected and healthy HIV-seronegative donors when exposed to HSV-1. The HSV-stimulated patients' PBMC exhibited less NK activity compared to similarly treated normal PBMC. These results suggest that a compromised ability of PBMC from HIV-infected individuals to induce IL-15 production in response to a viral stimulus may be a reason of t...
IL-15 and HIV Infection: Lessons for Immunotherapy and Vaccination
Current HIV Research, 2005
IL-15 is a pleiotropic and multifunctional cytokine that has a diverse array of distinct biological effects in the body. It plays a crucial role in host defense from viral and non-viral intracellular pathogens. The cytokine is essential for the development and differentiation of NK cells and for homeostatic expansion of CD8+ memory T cells, NKT cells and certain subsets of intestinal intra-epithelial lymphocytes (iIEL). It acts as a survival factor and inhibits spontaneous apoptosis in T, B and NK cells by increasing expression of different anti-apoptotic proteins. Several studies have shown that IL-15 production is compromised in HIV-infected AIDS patients and exogenous IL-15 drastically enhances functions of immune cells from these patients. Considering these distinct immune enhancing effects, relative safety in animal models, and minimal effects on HIV replication, IL-15 may represent a better cytokine for immune reconstitution in these patients. Furthermore, IL-15 may also act as a better adjuvant in eliciting antiviral immunity in anti-HIV vaccine strategies.
Interleukin-15 (IL-15) Strongly Correlates with Increasing HIV-1 Viremia and Markers of Inflammation
PloS one, 2016
IL-15 has been postulated to play an important role in HIV-1 infection, yet there are conflicting reports regarding its expression levels in these patients. We sought to measure the level of IL-15 in a large, well characterised cohort of HIV-1 infected patients and correlate this with well known markers of inflammation, including CRP, D-dimer, sCD163 and sCD14. IL-15 levels were measured in 501 people (460 patients with HIV-1 infection and 41 uninfected controls). The HIV-1 infected patients were divided into 4 groups based on viral load: <50 copies/ml, 51-10,000 copies/ml, 10,001-100,000 copies/ml and >100,000 copies/ml. The Mann Whitney test (non-parametric) was used to identify significant relationships between different patient groups. IL-15 levels were significantly higher in patients with viral loads >100,000 copies/ml (3.02 ± 1.53 pg/ml) compared to both uninfected controls (1.69 ± 0.37 pg/ml, p<0.001) or patients with a viral load <50 copies/ml (1.59 ± 0.40 pg...
AIDS Research and Human Retroviruses, 2012
Interleukin-15 (IL-15) enhances the effector mechanisms of anti-HIV immune responses and thus is considered a potential adjuvant of HIV-1 vaccine. However, there are a lack of data concerning the relationships between IL-15 expression and regulation in HIV-1-infected patients and the course of disease progression. We found that IL-15, but not IL-15Ra, is expressed at significantly higher levels in the CD14 + monocytes [stimulated or not with interferon (IFN)-c] of long-term nonprogressors (LTNP) than in those of HIV-1 progressors or healthy controls. There was no between-group difference in the amounts of soluble IL-15 released from the cells. We also found that like the healthy controls, the LTNP expressed the IL-15 and IL-15Ra genes in a more coordinated manner than the progressors. Our findings show that there are significant differences in IL-15 expression between patients with different courses of HIV infection, and that the coordinated expression of the IL-15 and IL-15Ra genes is dysregulated in patients with progressive disease. They also provide important information concerning the mechanisms of infection and the potential use of IL-15 as a therapeutic agent.
Clinical and Experimental Immunology, 1999
This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained from peripheral blood and lymphoid tissue from HIV+ individuals treated with highly active anti-retroviral therapy (HAART) alone or in combination with 6 million units international (MUI) s.c. IL-2. Before treatment, the HIV+ patients had reduced CD4 and increased CD8 values in the peripheral blood and lymphoid tissue and impaired cytokine production by peripheral blood mononuclear cells (PBMC). After 24 weeks of treatment, all the HIV+ patients demonstrated increased CD4 values in peripheral blood and lymphoid tissue. The use of IL-2 did not promote an additional CD4 expansion compared with HAART alone; increased ‘naive’ and CD26+ CD4 cells and reduced CD8 cells were found in the peripheral blood and lymphoid tissue of the IL-2-treated, but not of the HAART-treated patients. Both types of treatment induced a significant reduction of the CD8/CD38+ cells. While HAART alone had negligible e...
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2006
Antiretroviral therapy (ART) has led to marked decreases in morbidity and mortality rates among HIV-1Ypositive patients; however, immune recovery is not complete. Although dendritic cells (DCs) were shown to be involved in HIV-1 pathogenesis, few studies have investigated the effect of ART on DCs. We have analyzed the effect of ART on numerical distribution, expression of chemokine receptors, and ex vivo production of inflammatory cytokines by peripheral blood (PB) monocytes and DCs in a cohort of chronically infected HIV-1Ypositive patients. Patients were tested before therapy and at weeks +2, +4, +8, +12, and +52 after starting ART. Our results show an incomplete T-cell immune reconstitution in chronically infected patients who had undetectable plasma viremia while taking ART for 1 year. This was associated with persistent abnormalities at week +52 of ART, corresponding to increased numbers of CD16 + DCs and monocytes, as well as altered expression of CXC chemokine receptors, in the form of increased CXCR1 expression on monocytes and decreased reactivity for CXCR2 and/or CXCR4 on myeloid and plasmacytoid DCs. In addition, an abnormally high spontaneous ex vivo secretion of inflammatory cytokines by CD16 + DCs and monocytes was still detected after 1 year of ART. These abnormalities were especially pronounced in patients with less than 200 CD4 + T cells/KL, which could be related to the persistence of undetected viral replication and sustained immune activation.
The Journal of Infectious Diseases, 2003
Structured treatment interruption (STI) may help to alleviate the problems associated with long-term antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients. We analyzed the role that baseline levels of cytokines in plasma play as markers of a favorable outcome of STI. Two groups of patients were defined: STI responders and STI nonresponders. STI responders showed a higher baseline concentration of interleukin (IL)-15 in plasma than did STI nonresponders and showed lower levels of tumor necrosis factor (TNF)-a during STI. No differences were observed in levels of IL-2, IL-7, or interferon-a in plasma. Our data show that (1) levels of TNF-a in plasma correlate with HIV viremia and (2) monitoring baseline levels of IL-15 in plasma allows for the identification of a favorable outcome of STI. In a substantial proportion of human immunodeficiency virus (HIV)-infected individuals, antiretroviral therapy (ART) modifies the natural history of HIV infection, thereby producing remarkable benefits. However, most HIV-infected populations residing in developing countries have no access to continuous ART, and long-term therapy is limited by the need for strict daily adherence, occurrence of drug toxicity, elevated treatment costs, and sustained risks of emergence of drug resistance [1]. Structured treatment interruption (STI) may help to reduce