Decreased T Cell Apoptosis and T Cell Recovery during Highly Active Antiretroviral Therapy (HAART)

Ensoli, Fabrizio; Fiorelli, Valeria; Alario, C; Cristofaro, M. De; Muratori, Donatella Santini; Novi, Arianna; Cunsolo, Maria Giovanna; Mazzetta, Francesca; Giovannetti, Antonello; Mollicone, Bianca; Pinter, Elena; Aiuti, F

doi:10.1006/clim.2000.4915

Cited by 17 publications

(22 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Highly active antiretroviral therapy reduces apoptosis of HIV-specific T cells, as does PD-1 ligation, stimulation with IL-15, and inhibition of proapoptotic intracellular pathways [4,[10][11][12][13][14][15]. However, GITR triggering represents a novel means of preventing apoptosis of CD4 + T cells, one that appears to have a preferential impact on HIV-specific CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4⁺T Cell Cytokine Secretion and Protects HIV‐Specific CD4⁺T Cells from Apoptosis

Lahey¹,

Loisel

Wieland-Alter³

2007

J INFECT DIS

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV)-specific CD4(+) T cell cytokine secretion is characteristically weak during HIV infection, in part because HIV-specific CD4(+) T cells undergo massive apoptotic deletion. Glucocorticoid-induced tumor necrosis factor (TNF) receptor family-related (GITR) protein triggering enhances murine antigen-specific T cell cytokine secretion by protecting T cells from apoptosis. Therefore, we investigated the impact of GITR triggering on HIV-specific CD4(+) T cell cytokine secretion and on apoptosis of HIV-specific CD4(+) T cells. In HIV-infected subjects, CD4(+) T cell surface expression of GITR was greater than that in uninfected control subjects, and phytohemagglutinin induction of additional GITR expression was impaired. However, antibody triggering of GITR significantly increased HIV-specific CD4(+) T cell expression of TNF- alpha and interferon (IFN)- gamma . The percentage increase in HIV-specific CD4(+) T cell expression of TNF- alpha correlated directly with the absolute peripheral CD4(+) T cell count. Furthermore, GITR triggering reduced the expression of intracellular activated caspase-3 in HIV-specific CD4(+) T cells. Taken together, these data suggest that, despite abnormal GITR expression during HIV infection, GITR triggering enhances HIV-specific CD4(+) T cell cytokine expression and protects HIV-specific CD4(+) T cells from apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4⁺T Cell Cytokine Secretion and Protects HIV‐Specific CD4⁺T Cells from Apoptosis

Lahey¹,

Loisel

Wieland-Alter³

2007

J INFECT DIS

View full text Add to dashboard Cite

show abstract

“…5). In fact, it is well established that treatment results in reduction of both proliferation and death rates (22,36,37 ϩ and CD4 Ϫ T cells during infection, with different impacts on TREC per million cells in those two lymphocyte populations. Thus, discussions in terms of the effect of single processes on TREC should be taken with caution, because several processes-proliferation, death, thymic output, redistributionoccur simultaneously (9).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of T Cells and TCR Excision Circles Differ After Treatment of Acute and Chronic HIV Infection

Lewin

Ribeiro

Kaufmann

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

We quantified T cell proliferation and thymic function in primary HIV infection (PHI; n ‫؍‬ 19) and chronic HIV infection (CHI;n H uman immunodeficiency virus type 1 infection is marked by a progressive loss of CD4ϩ T cells, eventually leading to immunodeficiency and death. The pathogenesis of T cell depletion in HIV infection is complex, and debate continues as to whether T cell depletion is predominantly caused by increased T cell death, enhanced T cell proliferation and subsequent "exhaustion," or an inhibition of de novo T cell production (reviewed in Ref. 1). After effective antiretroviral therapy, this process is reversed in the majority of individuals and there is an increase in both CD4 ϩ naive and memory T cells and partial reconstruction of functional immunity (2).The role of the thymus in T cell homeostasis is critical to our understanding of T cell depletion, T cell turnover, and immune reconstitution. A fraction of recent thymic emigrants carries episomal TCR excision circles (TREC) 5 that do not replicate with cell division (3, 4). The number of TREC per million cells is dependent on thymic output, T cell proliferation, and the rate of death of both TREC-positive and -negative T cells. Hazenberg et al. (5) demonstrated an inverse relationship between the number of TREC per million cells and cell division in the naive T cell population from individuals with chronic HIV infection (CHI), suggesting that the reduction of TREC per million cells in HIV infection is a consequence of increased T cell proliferation and is not due to a reduction in thymic output. As suggested by Hazenberg et al. (5), interpretation of these results is complex because T cell proliferation, T cell death, and thymic function are all altered by HIV infection (6 -8) and, in addition, each of these processes will also affect the quantification of TREC (4, 9).To help unravel these competing processes we quantified TREC in two ways. First, we measured TREC per million T cells (CD4 ϩ and CD4 Ϫ ) and then, to account for changes in T cell number due to either HIV infection or therapy, we calculated TREC per milliliter of blood. Proliferation, for example, is thought to decrease TREC by dilution (5). This is clearly true if one measures TREC per million CD4 ϩ T cells, because division will not increase the number of TREC but will increase the number of cells. However, if one measures TREC per milliliter there will be no change because the number of TREC remains unchanged during cell division. If death occurs simultaneously with proliferation to maintain cell numbers, then TREC per milliliter will decrease as TREC ϩ

show abstract

“…48 The rapid and sustained increase in both naïve and memory CD4 cells, and also CD8 cells, in response to HAART was associated with a significant decrease in apoptotic CD4 and CD8 T cells. These findings indicate that viral suppression can help reduce T-cell abnormalities that cause high levels of CD4 cell apoptosis in HIV-infected individuals, and may contribute to the immunologic reconstitution observed during HAART.…”

Section: Reduction Of Apoptotic Cd4 Cellsmentioning

confidence: 93%

Review: Immunologic Response to Protease Inhibitor-Based Highly Active Antiretroviral Therapy: A Review

Wainberg

Clotet

2007

AIDS Patient Care and STDs

View full text Add to dashboard Cite

A substantial body of evidence indicates that CD4 cell count is an important independent prognostic indicator for progression of HIV disease. Consequently, in addition to plasma HIV RNA levels, CD4 cell count change is considered to be a key surrogate marker for disease progression in clinical practice and in clinical studies. Given the relationship between changes in CD4 count and disease progression, it is notable that protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) can rapidly increase CD4 cell count early in treatment in both therapy-naïve and -experienced patients, and can sustain clinically relevant levels beyond 24 weeks. A number of trials with a follow-up of more than 3 years allow us to conclude that the gains in CD4 counts are maintained in a durable manner. This review evaluated randomized studies of PI-based and PI-boosted HAART (published between January 1996 and February 2006) to determine the effect of PI-based therapy on CD4 cell count. Only studies that assessed CD4 response in the overall patient population were included. Four mechanisms have been proposed to account for the rapid increase in CD4 cell count that occurs with HAART: CD4 cell redistribution from lymphatic tissues, increased CD4 cell production, reduction of apoptotic CD4 cells and the recovery of hematopoietic activity in bone marrow. Further research is required to clarify the relative importance of these mechanisms and ways in which they might be enhanced.

show abstract

Decreased T Cell Apoptosis and T Cell Recovery during Highly Active Antiretroviral Therapy (HAART)

Cited by 17 publications

References 60 publications

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4⁺T Cell Cytokine Secretion and Protects HIV‐Specific CD4⁺T Cells from Apoptosis

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4⁺T Cell Cytokine Secretion and Protects HIV‐Specific CD4⁺T Cells from Apoptosis

Dynamics of T Cells and TCR Excision Circles Differ After Treatment of Acute and Chronic HIV Infection

Review: Immunologic Response to Protease Inhibitor-Based Highly Active Antiretroviral Therapy: A Review

Contact Info

Product

Resources

About

Decreased T Cell Apoptosis and T Cell Recovery during Highly Active Antiretroviral Therapy (HAART)

Cited by 17 publications

References 60 publications

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4+T Cell Cytokine Secretion and Protects HIV‐Specific CD4+T Cells from Apoptosis

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4+T Cell Cytokine Secretion and Protects HIV‐Specific CD4+T Cells from Apoptosis

Dynamics of T Cells and TCR Excision Circles Differ After Treatment of Acute and Chronic HIV Infection

Review: Immunologic Response to Protease Inhibitor-Based Highly Active Antiretroviral Therapy: A Review

Contact Info

Product

Resources

About

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4⁺T Cell Cytokine Secretion and Protects HIV‐Specific CD4⁺T Cells from Apoptosis

Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV‐Specific CD4⁺T Cell Cytokine Secretion and Protects HIV‐Specific CD4⁺T Cells from Apoptosis