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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We have reported previously the design of a RIAD (RI-anchoring disruptor) peptide that specifically displaces PKA (protein kinase A) type I from the AKAP (A-kinase-anchoring protein) ezrin, which is present in the immunological synapse of T-cells. This increases immune reactivity by reducing the threshold for activation and may prove a feasible approach for improving immune function in patients with cAMP-mediated T-cell dysfunction. However, the use of RIAD in biological systems is restricted by its susceptibility to enzymatic cleavage and, consequently, its short half-life in presence of the ubiquitous serum peptidases. In the present study, carefully selected non-natural amino acids were employed in the design of RIAD analogues with improved stability. The resulting peptidomimetics demonstrated up to 50-fold increased half-lives in serum compared with RIAD, while maintaining similar or improved specificity and potency with respect to disruption of PKA type I-AKAP interactions.

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.

The complexity of immunoregulation has focused attention on the CD4 1 T ''suppressor'' regulatory cell (T reg ), which helps maintain balance between immunity and tolerance. An immunoregulatory T-cell population that upon activation amplifies cellular immune responses was described in murine models more than 30 years ago; however, no study has yet identified a naturally occurring T ''inducer'' cell type. Here, we report that the ectoenzyme CD39/NTPDase1 (ecto-nucleoside triphosphate diphosphohydrolase 1) helps to delineate a novel population of human ''inducer'' CD4 1 T cells (T ind ) that significantly increases the proliferation and cytokine production of responder T cells in a dosedependent manner. Furthermore, this unique T ind subset produces a distinct repertoire of cytokines in comparison to the other CD4 1 T-cell subsets. We propose that this novel CD4 1 T-cell population counterbalances the suppressive activity of suppressor T reg in peripheral blood and serves as a calibrator of immunoregulation.Key words: CD25 . CD39 . FOXP3 . Inducer . Proliferation IntroductionNaturally occurring T reg constitute a suppressor T-cell population that play a pivotal role in maintaining the balance between tolerance and immunity. T reg can suppress effector T-cell responses, and dampen immune activation in various autoimmune, transplant and infectious disease states [1][2][3][4][5][6][7][8][9][10][11]. The existence of a reciprocal pathway of immune ''contrasuppression'' was first reported by seminal reports more than 30 years ago [12][13][14][15]. The description of a natural T ''inducer'' cell population that upon activation amplified cellular immune responses was suggested by clonal studies in mice [16]; however, such a natural SHORT COMMUNICATION 134population of T cells has not been clearly identified in mice or humans.The CD4 1 T-cell pool is diverse and plays important immunomodulatory roles in inflammation and infection. Naïve CD4 1 T cells are induced to differentiate toward Th1, Th2, Tr1, Th17 or T reg , each under a distinct transcriptional control, and dependent on the influence of mitogenic stimulation or a cytokine directed milieu [10,17,18]. Two recent studies highlight the importance of CD39/NTPDase1 as a useful biomarker for the identification of a CD4 1 regulatory suppressor T cell (T sup ) population with potent immunosuppressive activity in humans and mice [19,20]. CD39 is an endothelial cell membrane-associated nucleotidase initially described on B cell lines [21], and reported to play a dominant role in thromboregulation and vascular homeostasis [22,23].In this study, we characterize a novel CD4 1 inducer T-cell subset in humans, expressing CD39, which potently enhances T-cell immune responses that may be involved in the counterregulation of T reg . Results and discussionExpression of the CD39 molecule on CD3 1 T-cell subsetsTo investigate the expression of CD39 on lymphocyte subsets, we stained human PBMC and peripheral lymphoid cells from healthy individuals. We observed that the expression of C...