De novo T-cell generation in patients at different ages and stages of HIV-1 disease

Abstract

We assessed de novo T-cell generation by determining T-cell receptor-rearrangement excision circles (TRECs) based on patient age and on stage of HIV-1 infection. TRECs were measured in purified CD4 and CD8 T cells of a large cohort of HIV-1-infected subjects (n ‫؍‬ 297) with chronic infection but no previous antiretroviral treatment and of a control group of HIV-negative subjects (n ‫؍‬ 120). HIV-1-infected subjects were stratified on the basis of CD4 T-cell counts in 3 groups, early-stage disease (more than 500 CD4 T

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

“…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).…”

“…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 recent thymic emigrants (RTEs) as episomal DNA circles, do not replicate during mitosis, and are thus diluted during cell division (12).…”

Homeostasis of the Naive CD4+ T Cell Compartment during Aging

“…This has been shown by direct visualization and functional studies of thymocytes taken from adult thymic tissue (4 -6), as well as the detection of TCR excision circles (TRECs) 3 in the peripheral blood of the elderly (3). That the adult thymus retains the capacity to generate new T cells is perhaps best illustrated by studies demonstrating an increase in TREC content in the peripheral CD4 ϩ T cell compartment during highly active anti-retroviral therapy for HIV disease and following bone marrow transplantation into adults (7)(8)(9)(10)(11)(12).…”

Production of a Dendritic Cell-Based Vaccine Containing Inactivated Autologous Virus for Therapy of Patients with Chronic Human Immunodeficiency Virus Type 1 Infection

“…This vaccination strategy was found to be safe and feasible and resulted in a transient but significant increase in the frequency of CD8 ϩ T cells specific for HIV-1 peptides present in the vaccine (5). On the basis of the results of this trial, we have been considering a strategy of stimulating HIV-1-specific, naïve CD8 ϩ and CD4 ϩ T cells by priming them with DCs engineered to express autologous HIV-1 (19). The rationale for this strategy is that autologous virus represents a large repertoire of the host's diverse HIV-1 antigen pool and offers the potential to elicit the most specific, broadest, and most effective immune responses for each subject's quasispecies of HIV-1, thus increasing vaccine efficacy.…”