Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment

Kvale, Dag; Ormaasen, Vidar; Kran, Anne-Marte Bakken; Johansson, C. Christian; Aukrust, Pål; Aandahl, Einar Martin; Frøland, Stig S.; Taskén, Kjetil

doi:10.1097/01.aids.0000218544.54586.f1

Cited by 30 publications

(34 citation statements)

References 24 publications

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“…Paired statistics were therefore used to test changes within each study arm for most variables in the "as treated" analysis. COX-2i treatment further resulted in decreased serum IgA, in accordance with our previous observations of patients on ART (36). Since IgA is produced mainly at mucosal sites, COX-2 inhibition might reduce chronic immune activation in mucosal lymphoid compartments and counteract the translocation of microbial antigens typically observed in these patients (4,5,9,11,14,29,40,42,49).…”

Section: Discussionsupporting

confidence: 89%

“…Elevated levels of cAMP in T cells from HIV-infected individuals (2) may result from increased production of prostaglandin E 2 (PGE 2 ) in lymphoid tissues following activation-induced synthesis of cyclooxygenase type 2 (COX-2). Although we have identified COX-2-positive T cells in HIV-infected individuals (36), activated monocytes may be the major source of PGE 2 (25). High levels of COX-2 are produced de novo in monocytes, particularly upon exposure to LPS (10,27).…”

mentioning

confidence: 75%

“…Celecoxib was chosen because it had already been tested in patients on ART (36). The high dose of celecoxib may have caused the unexpected and relatively large number of generalized exanthemas (4 of 17 patients) compared to that in our previous study involving similar doses of celecoxib administered to patients on ART (0 of 19 patients; P Ͻ 0.05 by FiT) (36).…”

Section: Discussionmentioning

confidence: 99%

“…In two previous clinical exploratory trials, we demonstrated that COX-2 inhibition improved immune functions in HIV-positive patients on ART (30,36). In this trial, downregulation of chronic immune activation was assessed primarily by measuring CD38 on CD8 ϩ T cells.…”

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confidence: 98%

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An Exploratory Trial of Cyclooxygenase Type 2 Inhibitor in HIV-1 Infection: Downregulated Immune Activation and Improved T Cell-Dependent Vaccine Responses

Pettersen

Torheim

Dahm

et al. 2011

J Virol

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Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E 2 following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic immune activation in terms of CD38 density on CD8 ؉ T cells (؊24%; P ‫؍‬ 0.04), IgA levels (P ‫؍‬ 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8 ؉ T cells (P ‫؍‬ 0.01), including PD-1 on the HIV Gag-specific subset (P ‫؍‬ 0.02), enhanced the number of CD3 ؉ CD4 ؉ CD25 ؉ CD127 lo/؊ Treg or activated cells (P ‫؍‬ 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P ‫؍‬ 0.04). HIV RNA (P ‫؍‬ 0.06) and D dimers (P ‫؍‬ 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P ‫؍‬ 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection and improved T cell-dependent functions in vivo.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

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An Exploratory Trial of Cyclooxygenase Type 2 Inhibitor in HIV-1 Infection: Downregulated Immune Activation and Improved T Cell-Dependent Vaccine Responses

Pettersen

Torheim

Dahm

et al. 2011

J Virol

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“…Longitudinal studies of serum IgA and IgE levels in severely immunodeficient HIV-infected patients commencing ART are needed to address this issue. Indeed, the importance of obtaining longitudinal data was recently demonstrated in a study of the immunomodulatory effects of cyclooxygenase-2 inhibitors in HIV-infected patients receiving ART, where reductions in serum IgA levels were observed even though levels were within the reference interval [36].…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to opportunistic infections in HIV‐infected patients with increased CD4 T‐cell counts on antiretroviral therapy may be predicted by markers of dysfunctional effector memory CD4 T cells and B cells

et al. 2007

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ObjectivesHIV-infected patients responding to combination antiretroviral therapy (ART) after experiencing severe immunodeficiency may exhibit persistent immune defects and occasionally experience opportunistic infections (OIs) despite increased CD4 T-cell counts. The investigation of immune defects in such patients was examined in this study. Methods CD4 effector memory T-cell (T em -cell) function [assessed by blood cytomegalovirus (CMV)interferon-g (IFN-g) enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) counts] and B-cell dysregulation [assessed by serum immunoglobulin A (IgA) and IgE levels] were examined in 27 patients with increased CD4 T-cell counts after receiving ART for over 2 years. Two of these patients and one other had developed OIs on ART and are described in detail. ResultsSerum levels of IgA and IgE were higher than reference intervals (Po0.001) and CMV IFN-g ELISPOT counts were lower than those in non-HIV-infected controls (Po0.001) in the HIV-infected patients. Low CMV IFN-g ELISPOT counts were associated with high IgA levels (r 5 À 0.5, P 5 0.01, Spearman's correlation test) and segregated with high IgE levels (P 5 0.06, Fisher's test). CMV IFN-g ELISPOT counts and serum IgA and IgE levels did not change significantly over a median time of 35 (range 8-60) months after the first measurement, whereas CD4 T-cell counts increased. All three patients who experienced OIs had repeatedly low CMV IFN-g ELISPOT counts and increased serum levels of IgA and/or IgE. ConclusionLow CD4 T em -cell function and B-cell dysregulation are immune defects that may persist independently of changes in the CD4 T-cell count in HIV-1-infected patients responding to ART and are associated with an increased risk of developing an OI. Introduction HIV-1-infected patients receiving combination antiretroviral therapy (ART) who had a nadir CD4 T-cell count below 50 cells/mL may have persistent immune dysfunction despite increased CD4 T-cell counts [1][2][3][4]. A small proportion of such patients experience opportunistic infections (OIs) [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] [23,24]. High serum IgE levels are not associated with the production of allergen-specific IgE antibodies [25,26] and in some patients are associated with an immunodeficiency syndrome resembling hyper-IgE syndrome, where serum IgA levels may also be high [27]. Antiretroviral therapy only partly corrects the increased immunoglobulin production [28,29]. High serum IgA levels in HIV-infected patients receiving ART are associated with B-cell activation [29], but the fundamental cause and significance of these abnormalities remain unclear.Here, we describe the clinical and immunological findings in three HIV-infected patients who experienced recurrent or de novo Aspergillus fumigatus and/or Mycobacterium avium complex (MAC) infection whilst receiving long-term ART even though total CD4 T-cell counts had increased. We provide evidence that these patients had low CD4 T em -cell function associated with increased production of IgA a...

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Interleukin‐10‐secreting T cells define a suppressive subset within the HIV‐1‐specific T‐cell population

Torheim¹,

Ndhlovu²,

Pettersen³

et al. 2009

Eur J Immunol

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Recent studies have indicated that Treg contribute to the HIV type 1 (HIV‐1)‐related immune pathogenesis. However, it is not clear whether T cells with suppressive properties reside within the HIV‐1‐specific T‐cell population. Here, PBMC from HIV‐1‐infected individuals were stimulated with a 15‐mer Gag peptide pool, and HIV‐1‐specific T cells were enriched by virtue of their secretion of IL‐10 or IFN‐γ using immunomagnetic cell‐sorting. Neither the IL‐10‐secreting cells nor the IFN‐γ‐secreting cells expressed the Treg marker FOXP3, yet the IL‐10‐secreting cells potently suppressed anti‐CD3/CD28‐induced CD4+ as well as CD8+ T‐cell proliferative responses. As shown by intracellular cytokine staining, IL‐10‐ and IFN‐γ‐producing T cells represent distinct subsets of the HIV‐1‐specific T cells. Our data collectively suggest that functionally defined HIV‐1‐specific T‐cell subsets harbor potent immunoregulatory properties that may contribute to HIV‐1‐associated T‐cell dysfunction.

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Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment

Abstract: COX-2i together with CART improved markers for persistent immune activation, particularly in patients with viraemia, as well as enhanced perforin expression, and thereby strengthened COX-2 as a potential therapeutic target in HIV infection.

Cited by 30 publications

References 24 publications

An Exploratory Trial of Cyclooxygenase Type 2 Inhibitor in HIV-1 Infection: Downregulated Immune Activation and Improved T Cell-Dependent Vaccine Responses

An Exploratory Trial of Cyclooxygenase Type 2 Inhibitor in HIV-1 Infection: Downregulated Immune Activation and Improved T Cell-Dependent Vaccine Responses

Susceptibility to opportunistic infections in HIV‐infected patients with increased CD4 T‐cell counts on antiretroviral therapy may be predicted by markers of dysfunctional effector memory CD4 T cells and B cells

Interleukin‐10‐secreting T cells define a suppressive subset within the HIV‐1‐specific T‐cell population

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