Restoration of Normal Interleukin‐2 Production by CD4<sup>+</sup>T Cells of Human Immunodeficiency Virus–Infected Patients after 9 Months of Highly Active Antiretroviral Therapy

Weiss, Laurence; Ancuța, Petronela; Girard, Pierre‐Marie; Bouhlal, Hicham; Roux, Anne Françoise; Haeffner‐Cavaillon, Nicole; Kazatchkine, Michel D.

doi:10.1086/315025

Cited by 42 publications

(26 citation statements)

References 35 publications

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“…20,28,29 As we demonstrated a production of TGF-␤ and IL-10 by CD4 ϩ CD25 ϩ T cells isolated from HIV ϩ patients, we finally investigated the effect of blocking the secretion of TGF-␤ or IL-10 on the suppressive activity of CD4 ϩ CD25 ϩ T cells. We found that addition of neutralizing anti-TGF-␤ or anti-IL-10 mAbs, alone or in combination in a direct suppression assay, did not remove the suppressive activity of CD4 ϩ CD25 ϩ T cells on p24-specific CD4 ϩ CD25 Ϫ T-cell proliferation ( Figure 6).…”

Section: The Suppressive Activity Of Cd4 ؉ Cd25 ؉ T Cells From Hiv-inmentioning

confidence: 99%

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Weiss

Donkova-Petrini

Caccavelli

et al. 2004

Blood

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351

312

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The present study demonstrates that CD4 ؉ CD25 ؉ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4 ؉ CD25 ؉ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 ( IntroductionHIV infection is mainly associated with a progressive decrease in the number of CD4 ϩ T lymphocytes and defective CD4-specific and CD8-specific T-cell responses against HIV and other pathogens. It has been demonstrated that highly active antiretroviral therapy (HAART) results in reduced HIV-1 replication, increased CD4 cell counts in most treated patients, and progressive but incomplete recovery of CD4 ϩ T-cell functions. [1][2][3][4] Thus, treatment of chronic HIV infection does not result in most cases in a full recovery of HIV-specific helper and cytotoxic T lymphocyte (CTL) responses (reviewed in Sakaguchi et al 5 ).Recently, a CD4 ϩ T-cell subset with regulatory properties has been characterized in humans several years after their discovery in mice. [6][7][8][9][10] These cells, named "regulatory T" (Treg) cells express the ␣ chain of the interleukin 2 (IL-2) receptor (CD25) and can inhibit the proliferation of CD4 ϩ and CD8 ϩ T lymphocytes both in vitro and in vivo. 9,11 It has been demonstrated that transfer of such cells can protect neonatally thymectomized mice from autoimmune diseases, whereas their depletion results in the development of systemic autoimmune diseases. [12][13][14] Moreover, alloantigen-induced CD4 ϩ CD25 ϩ regulatory T cells were reported to prevent rejection initiated by CD4 ϩ cells in both organ and bone marrow transplantation. 15,16 Although CD25 is usually considered as an activation marker, it has been shown that CD4 ϩ CD25 ϩ lymphocytes do not proliferate in response to polyclonal, allogenic, or antigen-specific stimulation 8,9,17 but require activation through their T-cell receptor (TCR) to exert their suppressive function. Their anergic state could be partially reversed by IL-2 and IL-15. 9 Besides CD4 ϩ CD25 ϩ regulatory T cells, 2 other types of CD4 ϩ cells with suppressive function have been described: type 1 T regulatory (Tr1) cells 18 and T-helper 3 (Th3) cells. 19 Tr1 cells were reported to suppress the immune response via the secretion of the immunosuppressive cytokines IL-10 and transforming growth factor ␤ (TGF-␤). The mechanism by which CD4 ϩ CD25 ϩ T cells mediate suppression seems to require direct cell-cell contact. Levings et al 19 have recently demonstrated, at the clonal level, that Tr1 and CD4 ϩ CD25 ϩ T cells are distinct subsets of regulatory T cells and that the suppression mediated by CD4 ϩ CD25 ϩ T cells is partially dependent on TGF-␤.In healthy individuals, the CD4 ϩ CD25 ϩ T-cell subset represents 5% to 10% of peripheral CD4 ϩ T cells and is characterized by the constitutive expression of CD152 (CTL-associate...

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Section: The Suppressive Activity Of Cd4 ؉ Cd25 ؉ T Cells From Hiv-inmentioning

confidence: 99%

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Weiss

Donkova-Petrini

Caccavelli

et al. 2004

Blood

Self Cite

351

312

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“…Thymuses from pediatric patients undergoing an accelerated disease process (8,26,35,38) or from adults with AIDS (14,48) show severe thymocyte depletion associated with a profound disorganization of the thymic epithelial network. Thymic failure may also be responsible for the fact that, among patients undergoing antiretroviral therapies for advanced disease, the CD4 cell counts often remain below normal levels despite long-term suppression of viral load (32,62). Conversely, the levels of CD4 counts progressively increase in patients producing drug-resistant HIV strains which display low replication efficiencies in thymocytes (31,56).…”

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confidence: 99%

Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4⁺Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication

Schmitt

Chêne

Boutolleau

et al. 2003

J Virol

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The emergence of X4 human immunodeficiency virus type 1 (HIV-1) variants in infected individuals is associated with poor prognosis. One of the possible causes of this emergence might be the selection of X4 variants in some specific tissue compartment. We demonstrate that the thymic microenvironment favors the replication of X4 variants by positively modulating the expression and signaling of CXCR4 in mature CD4 ؉ CD8؊ CD3 ؉ thymocytes. Here, we show that the interaction of thymic epithelial cells (TEC) with these thymocytes in culture induces an upregulation of CXCR4 expression. The cytokine secreted by TEC, interleukin-7 (IL-7), increases cell surface expression of CXCR4 and efficiently overcomes the downregulation induced by SDF-1␣, also produced by TEC. IL-7 also potentiates CXCR4 signaling, leading to actin polymerization, a process necessary for virus entry. In contrast, in intermediate CD4 ؉ CD8 ؊ CD3 ؊ thymocytes, the other subpopulation known to allow virus replication, TEC or IL-7 has little or no effect on CXCR4 expression and signaling. CCR5 is expressed at similarly low levels in the two thymocyte subpopulations, and neither its expression nor its signaling was modified by the cytokines tested. This positive regulation of CXCR4 by IL-7 in mature CD4؉ thymocytes correlates with their high capacity to favor X4 virus replication compared with intermediate thymocytes or peripheral blood mononuclear cells. Indeed, we observed an enrichment of X4 viruses after replication in thymocytes initially infected with a mixture of X4 (NL4-3) and R5 (NLAD8) HIV strains and after the emergence of X4 variants from an R5 primary isolate during culture in mature thymocytes.

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“…Recent findings suggest that antiretroviral therapy can modify cytokine patterns, even if the exact mechanism is little known (23)(24)(25).…”

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confidence: 99%

Interleukin-4 and Interferon-Gamma Production during HIV-1 Infection and Changes Induced by Antiretroviral Therapy

Vecchiet

D’Alessandro

Travasi

et al. 2003

Int J Immunopathol Pharmacol

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Several lines of evidence indicate that a switch of the cytokine pattern from a predominant type 1 (antiviral and cell mediated response) to type 2 (polyclonal humoral immune response) occurs during the course of Human Immunodeficiency Virus-1 (HIV-1) infection, and represents a key event in the progression of immunodeficiency and dysregulated immune activation. We proposed to further investigate this immunological aspect of HIV-1 disease, in naive and in patients treated with Highly Active Antiretroviral Therapy (HAART). The prototypic cytokines chosen were Interleukin (IL)-4 and Interferon-gamma (IFN-γ), whose in vitro production was determined in mononuclear cell cultures stimulated with different T lymphocyte mitogenic agents (anti-CD3, Phytohaemoagglutin-P -PHA-, E. coli B04/035 Lipopolysaccharide -LPS-). We classified all the patients on the basis of the number of CD4+ lymphocytes and we found a progressive, even if not significant decrease in the baseline production of IFN-γ with the progression of the immunodeficiency. The mean value of baseline IFN-γ in the group of patients with CD4+>500 cells/μL was 7.79+3.1 pg/mL while in the group with CD4+<200 cells/μL it was 4.66±2.22. We didn't find significant differences in the baseline production of IL-4 in these groups and in IFN-γ and IL-4 production in LPS-stimulated cultures. We also re-assessed 12 patients after one year's follow-up. They presented a significant increase in IFN-γ production compared to the first assessment in the LPS-stimulated cultures (baseline IFN-γ 2.87+1.17 pg/mL, after 12 months 19.15±5.19 pg/mL; p= 0.03). In the 12 patients in follow-up IL-4 production showed a decreased in PHA-stimulated cultures with mean values of 16.65±14.32 pg/mL at baseline and 6.54±6.54 pg/mL after follow-up. These results highlight the immunorestoring effects of HAART. IL-4 production was lower in the treated subjects compared to the naive ones in PHA-stimulated cultures (mean values: IL-4=13.42 ±11.08 pg/mL in the naive patients and 9.75 ±65 pg/mL in the treated patients). The IFN-γ values in anti-CD3 stimulated cultures were also higher in the treated patients, but this increase was not significant.

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Restoration of Normal Interleukin‐2 Production by CD4⁺T Cells of Human Immunodeficiency Virus–Infected Patients after 9 Months of Highly Active Antiretroviral Therapy

Cited by 42 publications

References 35 publications

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4⁺Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication

Interleukin-4 and Interferon-Gamma Production during HIV-1 Infection and Changes Induced by Antiretroviral Therapy

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Restoration of Normal Interleukin‐2 Production by CD4+T Cells of Human Immunodeficiency Virus–Infected Patients after 9 Months of Highly Active Antiretroviral Therapy

Cited by 42 publications

References 35 publications

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4+Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication

Interleukin-4 and Interferon-Gamma Production during HIV-1 Infection and Changes Induced by Antiretroviral Therapy

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Product

Resources

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Restoration of Normal Interleukin‐2 Production by CD4⁺T Cells of Human Immunodeficiency Virus–Infected Patients after 9 Months of Highly Active Antiretroviral Therapy

Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4⁺Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication