Mechanisms Involved in the Low‐Level Regeneration of CD4<sup>+</sup>Cells in HIV‐1–Infected Patients Receiving Highly Active Antiretroviral Therapy Who Have Prolonged Undetectable Plasma Viral Loads

Benveniste, Olivier; Flahault, Antoine; Rollot, Florence; Elbim, Carole; Estaquier, Jérǒme; Pédron, Béatrice; Duval, Xavier; Dereuddre‐Bosquet, Nathalie; Clayette, Pascal; Sterkers, Ghislaine; Simon, Anne; Ameisen, Jean‐Claude; Leport, Catherine

doi:10.1086/429670

Cited by 111 publications

(77 citation statements)

References 34 publications

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“…This may be due to enhanced thymic output and/or to increased incorporation of the RTEs into the established pool of naïve CD4 ϩ T cells in these patients. In contrast, most previous studies indicating impaired thymic production in such patients have based their conclusions on the findings of either low TREC frequencies in CD4 ϩ T cells, or reduced absolute numbers of sjTRECs per microliter of blood (5,36,44). The absolute number of sjTRECs per microliter of blood depends on only the net balance between the input and output of sjTREC-bearing cells in the blood compartment, whereas sjTREC frequencies are also affected by T-cell proliferation (19,31).…”

Section: Our Investigation Of the Immunological And Virological Determentioning

confidence: 98%

“…Most studies have measured the signaljoint (sj) T-cell receptor (TCR) excision circle (TREC) in blood T cells. This surrogate marker of thymic activity is a byproduct of the TCR␦ locus rearrangement within the TCR␣ locus (␦Rec-J␣ rearrangement) that occurs during thymopoiesis (5,11,12,36,44). However, TRECs persist in recent thymic emigrants (RTEs) as episomal DNA circles, do not replicate during mitosis, and are thus diluted during cell division (12).…”

Section: The Reasons For Poor Cd4mentioning

confidence: 99%

See 1 more Smart Citation

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Delobel

Nugeyre

Cazabat

et al. 2006

J Virol

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The reasons for poor CD4؉ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeostasis during immune reconstitution on HAART. We examined this hypothesis and the mechanisms of CD4 ؉ T-cell restoration by comparing the virological and immunological features of 15 poor and 15 good immunological responders to HAART. We found a high frequency of X4 viruses in the poor immunological responders. But the levels of intrathymic proliferation of the two groups were similar regardless of whether they were infected by R5 or X4 virus. The frequency of recent thymic emigrants in the poor immunological responders was also similar to that found in the good immunological responders, despite their reduced numbers of naïve CD4 ؉ T cells. Our data, rather, suggest that the naïve T-cell compartment is drained by a high rate of mature naïve cell loss in the periphery due to bystander apoptosis or activation-induced differentiation. X4 viruses could play a role in the depletion of naïve T cells in poor immunological responders to HAART by triggering persistent T-cell activation and bystander apoptosis via gp120-CXCR4 interactions.Highly active antiretroviral therapy (HAART) successfully controls human immunodeficiency virus type 1 (HIV-1) replication in most individuals, resulting in substantial immune restoration and decreased morbidity and mortality. However, the suppression of detectable HIV-1 viremia does not invariably result in a significant increase in CD4 ϩ T cells. Five to 15% of HIV-infected patients still have a CD4ϩ T-cell counts of Ͻ200 cells/l and are thus at risk of developing AIDS, despite being on HAART for several years (15, 23).The mechanisms responsible for these persistently low CD4 ϩ T-cell counts are not clear; they could be due to impaired reconstitution or to excessive destruction of CD4 ϩ T cells. The recovery of peripheral CD4 ϩ T-cell counts in patients on HAART depends mainly on a slow increase in naïve CD4 ϩ T cells (3). Several studies have suggested that the thymus plays a role in immune reconstitution during HIV-1 infection, even in adults (12,34,36), but the extent to which it determines the regeneration of the peripheral CD4 ϩ T-cell pool in patients on HAART remains unclear. Analyses of thymic activity are hampered by the difficulty of directly measuring thymic output. Most studies have measured the signaljoint (sj) T-cell receptor (TCR) excision circle (TREC) in blood T cells. This surrogate marker of thymic activity is a byproduct of the TCR␦ locus rearrangement within the TCR␣ locus (␦Rec-J␣ rearrangement) that occurs during thymopoiesis (5,11,12,36,44). However, TRECs persist in recen...

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Section: Our Investigation Of the Immunological And Virological Determentioning

confidence: 98%

Section: The Reasons For Poor Cd4mentioning

confidence: 99%

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Delobel

Nugeyre

Cazabat

et al. 2006

J Virol

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“…More than one-fourth of the patients after years of HAART still have CD4 T-cell counts not significantly increased from pretreatment levels and/ or below the critical threshold of 200 cells/mm 2 ; and even in patients with significant increases in peripheral CD4 T-cell counts, few reach the levels in uninfected populations after long-term HAART. [2][3][4][5][6][7][8][9][10] Limited immune reconstitution is most prevalent in patients starting HAART in the chronic stage of disease (CD4 Ͻ 350 cells/ L) and in older age patients, and this failure in reconstitution strongly correlates with significantly higher morbidity and mortality. [4][5][6]9,[11][12][13] Further, the magnitude of CD4 ϩ T-cell reconstitution in peripheral blood does not necessarily reflect the real magnitude of immune reconstitution in lymphoid tissues (LTs) where these cells mostly reside.…”

Section: Introductionmentioning

confidence: 99%

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Zeng

Paiardini

Engram

et al. 2012

Blood

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“…However, other studies measuring TREC levels and immune recovery after HAART have used small sample sizes of good and poor immune recovery, 19 NR and 19 SR patients in the study by Benveniste et al (18) and 10 NR and 12 SR patients in the study by Teixeira et al (19).…”

Section: Discussionmentioning

confidence: 99%

Thymic Function during 12 Months of Highly Active Antiretroviral Therapy in Thai HIV-Infected Patients with Normal and Slow Immune Recovery

et al. 2015

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SUMMARY:The aim of this study was to determine and compare thymic output during 12 months of highly active antiretroviral therapy (HAART) in HIV-infected patients with different types of immune recovery. In total, 18 Thai HIV-infected patients with normal immune recovery (NR) and 13 Thai HIVinfected patients with slow immune recovery (SR) were enrolled. T-cell receptor rearrangement excision circle (TREC) levels in peripheral blood mononuclear cells (PBMCs) and CD4 ＋ T cells were quantified at baseline, and after 6 and 12 months of HAART. CD4 ＋ T-cell counts in NR patients were significantly higher than those in SR patients after 6 and 12 months of HAART. However, the median TREC levels in PBMCs and CD4 ＋ T cells in both groups were comparable. Moreover, TREC levels showed similar trends in PBMCs and CD4 ＋ T cells in both groups during 12 months of HAART. Only patients with SR had significant increases in median TREC levels in PBMCs and CD4

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Mechanisms Involved in the Low‐Level Regeneration of CD4⁺Cells in HIV‐1–Infected Patients Receiving Highly Active Antiretroviral Therapy Who Have Prolonged Undetectable Plasma Viral Loads

Abstract: The mechanisms responsible for the low-level regeneration of CD4(+) cells involve, at least, deficiency in the regeneration of central CD4(+) cells and excessive apoptosis.

Cited by 111 publications

References 34 publications

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Thymic Function during 12 Months of Highly Active Antiretroviral Therapy in Thai HIV-Infected Patients with Normal and Slow Immune Recovery

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Mechanisms Involved in the Low‐Level Regeneration of CD4+Cells in HIV‐1–Infected Patients Receiving Highly Active Antiretroviral Therapy Who Have Prolonged Undetectable Plasma Viral Loads

Abstract: The mechanisms responsible for the low-level regeneration of CD4(+) cells involve, at least, deficiency in the regeneration of central CD4(+) cells and excessive apoptosis.

Cited by 111 publications

References 34 publications

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Thymic Function during 12 Months of Highly Active Antiretroviral Therapy in Thai HIV-Infected Patients with Normal and Slow Immune Recovery

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Product

Resources

About

Mechanisms Involved in the Low‐Level Regeneration of CD4⁺Cells in HIV‐1–Infected Patients Receiving Highly Active Antiretroviral Therapy Who Have Prolonged Undetectable Plasma Viral Loads