Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy

Piconi, Stefania; Trabattoni, Daria; Gori, Andrea; Parisotto, Serena; Magni, C.; Meraviglia, Paola; Bandera, Alessandra; Capetti, Amedeo; Rizzardini, Giuliano; Clerici, Mario

doi:10.1097/qad.0b013e32833c93ce

Cited by 120 publications

(106 citation statements)

References 49 publications

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“…+ T cell nadir and a poor immunological response to HAART [27,28,39,41,42]. In particular, Mendes-Lagares et al have pointed out the role of Tregs in the control of naive CD4…”

Section: Discussionmentioning

confidence: 99%

“…We observed that effector and terminal effector Tregs were increased significantly in iIR compared to cIR, which was never pointed elsewhere. Very few data are available concerning those Treg subsets in HIV-infected patients [39,50]. Effector Tregs have been studied in the peripheral blood mononuclear cells of 18 aviraemic patients with a good immunological response to HAART [50].…”

Section: Discussionmentioning

confidence: 99%

“…However, the most widely accepted phenotype for Tregs is the co-expression of CD4, CD25 (α-chain of the IL-2 receptor), and of FoxP3, even in HIV-infected patients [14,36,38,39,48,49]. We took advantage of recent progresses in intracellular FoxP3 staining in whole blood to reduce pre-analytical procedures that may interfere with interpretation of the results [38].…”

Section: Discussionmentioning

confidence: 99%

“…This agrees with previous results. In particular, an increased age has been found by others to be associated with IR [39,40]. Thus, a multivariate model adjusted on age, nadir of CD4 + T cell count, Tregs and CD8 + CD38 + T cell percentages was performed.…”

Section: Parameters Associated With Immunological Response To Haartmentioning

confidence: 99%

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Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Saison

Ferry

Demaret

et al. 2014

Clinical and Experimental Immunology

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SummaryThe mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (Tregs) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4 + T cell count (> or < 500/mm 3 ). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4 + lymphocytes, including Treg subsets, and CD8 + T cells was performed. Percentages of activated CD4 + T cells, Tregs, effector Tregs and terminal effector Tregs were found to be significantly elevated in iIR. Neither the percentage of activated CD8+ T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4 + T cell count and percentage of Tregs were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4 + and CD8+ T cells, Treg percentages and very low-level viraemia. Causative interactions between Tregs and CD4 + T cells should now be explored prospectively in a large patients cohort.

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“…+ T cell nadir and a poor immunological response to HAART [27,28,39,41,42]. In particular, Mendes-Lagares et al have pointed out the role of Tregs in the control of naive CD4…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Parameters Associated With Immunological Response To Haartmentioning

confidence: 99%

See 2 more Smart Citations

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Saison

Ferry

Demaret

et al. 2014

Clinical and Experimental Immunology

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“…HIV-infected individuals receiving cART continue to have a significantly shorter life expectancy, even in settings of advanced medical care (1), and they experience higher rates of non-AIDS comorbidities such as cardiovascular disease and non-AIDS cancers (2-5), many of which have an inflammatory etiology and may be related to continuing immunodeficiency (5). The success in reconstituting a functional immune system, defined by restoration of CD4 T cell counts following cART, is limited by immune activation and associated with pre-cART endotoxemia (6,7).…”

mentioning

confidence: 99%

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Lichtfuss

Cheng

Farsakoglu

et al. 2012

The Journal of Immunology

109

106

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FcRγ is an ITAM-containing adaptor required for CD16 signaling and function in NK cells. We have previously shown that NK cells from HIV patients receiving combination antiretroviral therapy (cART) have decreased FcRγ expression, but the factors causing this are unknown. We conducted a cross-sectional study of cART-naive viremic patients (ART−), virologically suppressed patients receiving cART (ART+), and HIV-uninfected controls. CD8+ T cells were activated, as assessed by CD38+HLA-DR+ expression, in ART− patients (p < 0.0001), which was significantly reduced in ART+ patients (p = 0.0005). In contrast, CD38+HLA-DR+ NK cells were elevated in ART− patients (p = 0.0001) but did not decrease in ART+ patients (p = 0.88). NK cells from both ART− and ART+ patients showed high levels of spontaneous degranulation in ex vivo whole blood assays as well as decreased CD16 expression (p = 0.0001 and p = 0.0025, respectively), FcRγ mRNA (p < 0.0001 for both groups), FcRγ protein expression (p = 0.0016 and p < 0.0001, respectively), and CD16-dependent Syk phosphorylation (p = 0.0001 and p = 0.003, respectively). HIV-infected subjects showed alterations in NK activation, degranulation, CD16 expression and signaling, and elevated plasma markers of inflammation and macrophage activation, that is, neopterin and sCD14, which remained elevated in ART+ patients. Alterations in NK cell measures did not correlate with viral load or CD4 counts. These data show that in HIV patients who achieve viral suppression following cART, NK cell activation persists. This suggests that NK cells respond to factors different from those driving T cell activation, but which are associated with inflammation in HIV patients.

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Hepatitis C Virus Infection and Coinfection With Human Immunodeficiency Virus

Hadigan

Kottilil²

2011

JAMA

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Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) both emerged in the second half of the 20th century, and chronic infection with these agents is among the greatest challenges facing health care in the United States and worldwide. Despite tremendous advances in treatment and management of HIV and HCV, individuals with HIV/HCV coinfection experience a more complicated disease course and treatment. Recognition of the important role that host factors, such as IL28B genotype, have in response to HCV therapy and the emergence of new effective therapies for HCV are actively reshaping the standard of care. These advances may translate into more effective treatment and management of patients with chronic HCV and HIV coinfection in the years ahead.

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Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy

Abstract: Lack of CD4 recovery in individuals in whom ART suppresses HIV replication is associated with complex immune alterations. Immune activation, likely driven by altered gut permeability and resulting in augmented Treg activity could play a pivotal role in this process.

Cited by 120 publications

References 49 publications

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Hepatitis C Virus Infection and Coinfection With Human Immunodeficiency Virus

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