Increased thymic output after initiation of antiretroviral therapy in human immunodeficiency virus type 1-infected children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 Trial

To investigate the thymic contribution to immune reconstitution during antiretroviral therapy (ART), T cell receptor gene rearrangement excision circles (TRECs) were measured in peripheral blood mononuclear cells (PBMC) and CD4 cells from 33 human immunodeficiency virus (HIV) type 1-infected children monitored for 96 weeks after ART initiation. Baseline TREC levels were associated positively with baseline CD4 cell percentage and inversely with age and HIV-1 RNA load. During therapy, TREC level changes in PBMC and CD4 cells were fairly comparable. TREC level changes were inversely related to baseline CD4 cell percentage and positively associated with CD4 cell percentage increases, the main source being naive CD4 cells. TREC changes were independent of age and baseline HIV-1 RNA load; however, HIV-1 suppression was independently associated with smaller TREC changes. Thymic output appears to be the main source of CD4 cell repopulation in children receiving ART. Recovery of thymic function is independent of age and influenced by the status of peripheral CD4 cell depletion and HIV-1 suppression.     

Identification of non-naïve CD4+CD45RA+ T cell subsets in adult allogeneic haematopoietic cell transplant recipients

The study of thymic-dependent pathways of T cell reconstitution in T cell replete haematopoietic cell transplant (HCT) recipients in previous studies was complicated by the transfer of na?ve CD4(+)CD45RA(+) T cells with the stem cell graft. However, direct quantification of thymic output has been enabled by measurement of T cell receptor excision circles (TREC). We analysed T cell reconstitution using T cell phenotyping and TREC quantification in 12 T cell-replete HCT recipients 6-53 years of age during the first 12 months post transplant. We have identified a novel subpopulation of CD4(+)CD45RA(+) T cells in the peripheral blood of these HCT recipients with expansions of this subset being more pronounced in older recipients. The recovery of classical na?ve CD4(+)CD45RA(+) T cells was dependent on thymic output whereas this novel CD4(+)CD45RA(+) subpopulation arose independently of thymic output and displayed effector function and phenotype. These results suggest that CD4(+)CD45RA(+) effector populations exist, similar to the CD8(+)CD45RA(+) effector subset, and that the CD45RA antigen should not be used alone to define na?ve CD4(+) T cells when monitoring T cell reconstitution in T cell replete HCT recipients. Furthermore, these results raise important questions regarding the role of the thymus in regulating T cell homeostasis in older HCT recipients and normal individuals.     

T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events

It is generally believed that homeostatic responses regulate T-cell recovery after peripheral stem cell transplantation (PSCT). We studied in detail immune recovery in relation to T-cell depletion and clinical events in a group of adult patients who underwent PSCT because of hematologic malignancies. Initially, significantly increased proportions of dividing naive, memory, and effector CD4(+) and CD8(+) T cells were found that readily declined, despite still very low numbers of CD4(+) and CD8(+) T cells. After PSCT, increased T-cell division rates reflected immune activation because they were associated with episodes of infectious disease and graft-versus-host disease (GVHD). T-cell receptor excision circles (TRECs) were measured to monitor thymic output of naive T cells. Mean TREC content normalized rapidly after PSCT, long before naive T-cell numbers had significantly recovered. This is compatible with the continuous thymic production of TREC(+) naive T cells and does not reflect homeostatic increases of thymic output. TREC content was decreased in patients with GVHD and infectious complications, which may be explained by the dilution of TRECs resulting from increased proliferation. Combining TREC and Ki67 analysis with repopulation kinetics led to the novel insight that recovery of TREC content and increased T-cell division during immune reconstitution after transplantation are related to clinical events rather than to homeostatic adaptation to T-cell depletion. (Blood. 2002;99:3449-3453)     

Reduced-intensity conditioning regimen preserves thymic function in the early period after hematopoietic stem cell transplantation

OBJECTIVE: To compare T-cell reconstitution in two groups of patients submitted to allogeneic stem cell transplantation (SCT): those receiving reduced-intensity conditioning (RIC, n = 24) and those receiving myeloablative conditioning (MA, n = 27). METHODS: Fifty-one consecutive patients undergoing SCT were evaluated. Serial assessments of lymphocyte subsets and T cell receptor excision circles (TRECs) levels were performed using multiparametric flow cytometry and real-time PCR, respectively. RESULTS: During the first 6 months posttransplant, total and na?ve CD4(+) T cell counts were higher after RIC-SCT than after MA-SCT (total CD4(+): p = 0.04, p = 0.08, and p = 0.058; na?ve CD4(+): p = 0.14, p = 0.05, and p = 0.01 at 1, 3, and 6 months, respectively). In both groups of patients, TRECs levels were low or undetectable in the first 3 months after SCT and progressively increased during the study. However, a higher proportion of patients with detectable levels of TRECs was observed in RIC-SCT at 1 and 3 months and more patients in this group reached normal levels of TRECs at 6 months post-SCT. In the multivariate analysis, including factors such as type of donor (sibling vs unrelated), dose of CD34(+) cells infused with the graft, patient age, and graft-vs-host disease (GVHD), the most important factor influencing TRECs recovery in the early period after SCT was the type of conditioning regimen. CONCLUSIONS: In this study, the pattern of immune reconstitution after RIC-SCT was different from that of MA-SCT and was characterized by higher posttransplant na?ve CD4(+) T cell counts and TRECs levels in the early period after transplant.     

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

The factors affecting T cell reconstitution post haematopoietic cell transplantation (HCT) are not well characterised. We carried out a longitudinal analysis of T cell reconstitution in 32 HCT recipients during the first 12 months post transplant. We analysed reconstitution of na?ve, memory and effector T cells, their diversity and monitored thymic output using TCR rearrangement excision circles (TRECs). Thymic-independent pathways were responsible for the rapid reconstitution of memory and effector T cells less than 6 months post HCT. Thymic-dependent pathways were activated between 6 and 12 months in the majority of patients with na?ve T cell numbers increasing in parallel with TREC levels. Increasing patient age, chronic GVHD and T cell depletion (with or without pretransplant Campath-1H) predicted low TREC levels and slow na?ve T cell recovery. Furthermore, increasing patient age also predicted high memory and effector T cell numbers. The effects of post HCT immunosuppression, total body irradiation, donor leucocyte infusions, T cell dose and post HCT infections on T cell recovery were also analysed. However, no effects of these single variables across a variety of different age, GVHD and T cell depletion groups were apparent. This study suggests that future analysis of the factors affecting T cell reconstitution and studies aimed at reactivating the thymus through therapeutic intervention should be analysed in age-, GVHD- and TCD-matched patient groups.     

Evidence of thymic function in heavily antiretroviral-treated human immunodeficiency virus type 1-infected adults with long-term virologic treatment failure

Thymic function was evaluated in 32 heavily antiretroviral-treated human immunodeficiency virus type 1 (HIV-1)-infected adults with long-term virologic treatment failure by measuring thymic volume, by determining the absolute number of naive T cell phenotypes, and by determining the number of cells carrying T cell receptor excision circles (TRECs). There was a significant inverse correlation between age and thymic volume (r=-0.415; P=.018), and there was a significant direct correlation between thymic volume and total naive T cell counts (r=0.529; P=.002), naive CD4(+) cell counts (r=0.437; P=.012), naive CD8(+) cell counts (r=0.467; P=.007), and TREC levels (r=0.391; P=.027). In conclusion, this study found clear evidence that the thymus of heavily antiretroviral-treated HIV-1-infected adults with long-term virologic treatment failure is actively engaged in thymopoiesis, which generates new naive T cells for the peripheral lymphocyte pool.     

Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness

OBJECTIVE: To investigate the role of thymic output and viral fitness in immune reconstitution in HIV-1-infected children on antiretroviral therapy. METHODS: Thymic output was studied by measuring levels of T-cell receptor rearrangement excision circles (TREC) in peripheral blood lymphocytes, using a real-time quantitative PCR assay. Recombinant viruses containing pre-therapy or post-therapy HIV-1 protease domains were evaluated for viral infectivity in a quantitative single-cycle assay. RESULTS: Eighteen HIV-1-infected children who showed a significant increase in CD4 T-cell count after therapy were studied; HIV-1 plasma viraemia was substantially suppressed in 12 children (virological responders), but not in the other six (virological non-responders). TREC were quantified at baseline, and sequentially during the first 12 months of therapy. Both virological responders and non-responders showed an increase in TREC levels that was inversely correlated with baseline TREC and CD4 T cell counts. Changes in TREC positively correlated with CD4 T-cell count increases in virological responders, but not in non-responders; moreover, the ratios between TREC and CD4 T-cell count increases were higher in non-responders than in responders, suggesting a persistence of peripheral CD4 T-cell loss in the former. Drug-resistant viruses with reduced replicative capacity were documented in three out of six non-responders. CONCLUSIONS: These findings indicate that recovery of thymic function is a pivotal event in immune reconstitution, and suggest that CD4 T-cell increase despite persistent viraemia is sustained by a continuous thymic output that compensates peripheral CD4 T-cell depletion which might be slowed down by emerging viruses with reduced fitness.     

Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults

Following myeloablative therapy, it is unknown to what extent age-dependent thymic involution limits the generation of new T cells with a diverse repertoire. Normal T-cell receptor gene rearrangement in T-cell progenitors results in the generation of T-cell receptor rearrangement excision circles (TRECs). In this study, a quantitative assay for TRECs was used to measure T-cell neogenesis in adult patients with leukemia who received myeloablative therapy followed by transplantation of allogeneic hematopoietic stem cells. Although phenotypically mature T cells had recovered by 1 to 2 months after bone marrow transplantation (BMT), TREC levels remained low for 3 months after BMT. T-cell neogenesis became evident by 6 months, and normal levels of adult thymic function were restored at 6 to 12 months after BMT. Subsequent leukemia relapse in some patients was associated with reduced TREC levels, but infusion of mature donor CD4(+) T cells resulted in rapid restoration of thymic function. These studies demonstrate that T-cell neogenesis contributes to immune reconstitution in adult patients and suggest that thymic function can be manipulated in vivo. (Blood. 2001;98:1116-1121)     

Effects of exogenous interleukin-7 on human thymus function

Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a(+)CD3(-)CD4(+)CD8(+) stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3(-) cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-alphabeta rearrangement and indicate the potential use of IL-7 for enhancing de novo na?ve T-cell generation in immunocompromised patients.     

Thymic output during initial highly active antiretroviral therapy (HAART) and during HAART supplementation with interleukin 2 and/or with HIV type 1 immunogen (Remune)

The thymic output of patients receiving highly active antiretroviral therapy (HAART) was assessed by sjTREC (signal joint T cell receptor rearrangement excision circle) analysis to determine the thymic contribution to CD4(+) T cell reconstitution during initial therapy and during interleukin 2 (IL-2) and/or Remune supplementation of HAART. Levels of sjTRECs were observed to decline dramatically after the first 4 weeks of HAART and then increased without significant associated changes in CD4(+) T cell counts. HAART supplementation with IL-2 was observed to lead to rapid increases in CD4(+) T cells that were accompanied by sjTREC decreases. No notable changes in CD4(+) T cell counts and sjTRECs were seen in patients receiving HAART supplemented with Remune alone. The results indicate CD4(+) T cell maintenance during initial treatment of HIV-1 with HAART and early CD4(+) T cell reconstitution of patients receiving IL-2 with HAART is largely due to thymus-independent mechanisms, with the thymus making a limited contribution.     

Association between larger thymic size and higher thymic output in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy

To examine the impact of thymic size on immune recovery in patients with human immunodeficiency virus (HIV) infection, the thymus was visualized, using computed tomographic scans, in 25 HIV-infected patients who had received highly active antiretroviral therapy (HAART) for 6-18 months and had levels of viremia <500 copies/mL. For comparison, 10 control subjects were included in the study. Total and naive CD4+ cell counts were determined by flow cytometry. To determine thymic output, the number of CD4+ cells containing T cell receptor excision circles (TRECs) was measured. Qualitative immune recovery was evaluated by determination of CD4+ T cell receptor repertoire in 19 of the HIV-infected patients. Larger thymic size was associated with higher CD4+ cell counts (r=0.498; P=.011) and higher CD4+ TREC frequency (r=0.652; P<.001). Furthermore, patients with abundant thymic tissue seemed to have broader immunologic repertoires, compared with patients with minimal thymic tissue (P=.054). These findings suggest that thymopoiesis is ongoing in the adult thymus and contributes to immune reconstitution in HIV-infected patients receiving HAART.     

Endogenous IL-7 is associated with increased thymic volume in adult HIV-infected patients under highly active antiretroviral therapy

OBJECTIVE: Immune reconstitution after highly active antiretroviral therapy (HAART) in HIV-infected patients has led to an increase in the number of new CD4 T lymphocytes. Neolymphopoiesis in the thymus has been proposed as a mechanism in T-cell regeneration. Nevertheless, factors involved in the regeneration of T cells by thymic-dependent pathways in HIV-infected patients under HAART are still unknown and might be of relevance in HIV infection. The aim of this work was to study the role of IL-7 in the thymic rebound of HIV-infected adults under HAART. DESIGN: To study the association between IL-7 and thymic function-related markers, these variables were measured in 49 antiretroviral-naive HIV-infected patients at baseline and at weeks 12, 24, 36 and 48 of treatment. METHODS: Thymic function-related markers: thymic volume, naive phenotype, and T-cell receptor excision circles (TREC) bearing-cells, were evaluated by computed tomography, flow cytometry, and quantitative polymerase chain reaction, respectively. IL-7 levels were evaluated using a high sensitivity colorimetric enzyme-linked immunosorbent assay. RESULTS: At baseline, we found an inverse correlation between IL-7 levels and thymic function-associated parameters: thymic volume, naive T cells and TREC-bearing cells. After 48 weeks of therapy increased levels of thymic function-related markers along with a significant decrease in IL-7 levels were found. IL-7 levels at baseline were the only independently associated variable with respect to changes in thymic volume at weeks 12, 24 and 48 of follow-up. CONCLUSION: These data suggest that IL-7 plays an important role in thymic rebound in adult HIV-infected patients under HAART.     

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and na?ve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of na?ve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the na?ve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of na?ve CD4+ T cells at baseline resulted in modest long-term na?ve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Na?ve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.     

Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients

Objectives To examine the extent of immune reconstitution in treatment‐naive patients with CD4 T‐cell counts <500 cells/μL following 48 weeks of highly active antiretroviral therapy (HAART). Methods Thirteen antiretroviral naive patients were evaluated longitudinally for 48 weeks on HAART utilizing immune functional and lymphocyte phenotyping assays, including lymphocyte proliferation assay, flow cytometric evaluation of cell surface markers, and delayed type hypersensitivity skin tests. Virologic responses were monitored using commercially available viral load assays and gag/pol mRNA quantification using simultaneous immunophenotyping/UltraSensitive fluorescence in situ hybridization (ViroTect In Cell HIV‐1 Detection Kit; Invirion, Frankfort, MI). Thymic function was evaluated for a subset of four patients using real‐time polymerase chain reaction (PCR) for T‐cell receptor excision circle (TREC) quantification and thymic scans using computerized axial tomography (CT) of the thymus. Results HAART initiation resulted in a significant decline in plasma viremia and percentage of infected peripheral blood cells, and a rise in CD4 T cells from a baseline median of 207 cells/μL to a week‐48 median of 617 cells/μL. The rise was predominately in CD4 memory cells. Naive T cells also increased in number, but at a slower rate. Activated (HLA‐DR CD38) CD4 and CD8 T cells were elevated at baseline (24 and 62%, respectively) and declined by week 48 (17 and 36%, respectively) but did not reach normal levels. The number of Fas CD4 T cells increased from a baseline median of 169 to 381 cells/μL at week 48. Both soluble interleukin (IL)‐2 and tumour necrosis factor (TNF) II receptors declined by week 48. HIV p24 lymphocyte proliferation assay responses were transiently detected in three patients. TREC values increased from a median 6400 copies/μg at baseline to a week‐48 median value of 26 697 copies/μg. Conclusion Immune functional reconstitution was not achieved in these HAART naive patients.     

Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations

Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution of normal T-cell immunity. Recipient thymic activity, biologic features of the allograft, and preparative regimens all contribute to immune reconstitution. We evaluated circulating T-cell phenotypes and T-cell receptor rearrangement excision circles (TRECs) in 331 blood samples from 158 patients who had undergone allogeneic HSCTs. All patients had received myeloablative conditioning regimens and were full donor chimeras in remission. Younger patients exhibited more rapid recovery and higher TRECs (P =.02). Recipients of T-cell-depleted allografts initially had lower TRECs than unmodified allograft recipients (P <.01), but the difference abated beyond 9 months. TREC level disparities did not achieve significance among adults with respect to type of allograft. Measurable, albeit low, TREC values correlated strongly with severe opportunistic infections (P <.01). This finding was most notable during the first 6 months after transplantation, when patients are at greatest risk but before cytofluorography can detect circulating CD45RA(+) T cells. Low TRECs also correlated strongly with extensive chronic graft-versus-host disease (P <.01). Recipients of all ages of either unmodified or T-cell-depleted allografts therefore actively generate new T cells. This generation is most notable among adult recipients of T-cell-depleted allografts, most of whom had also received antithymocyte globulin for rejection prophylaxis. Low TREC values are significantly associated with morbidity and mortality after transplantation. T-cell neogenesis, appropriate to age but delayed in adult recipients of T-cell-depleted allografts, justifies interventions to hasten this process and to stimulate desirable cellular immune responses.     

Evaluation of T cell receptor gene rearrangement excision circles after antiretroviral therapy in children infected with human immunodeficiency virus

Immune reconstitution after antiretroviral therapy in human immunodeficiency virus (HIV)infected patients may result from the recovery of thymus function, peripheral redistribution, or decreased T cell destruction. This study investigated levels of T cell receptor gene rearrangement excision circles (TRECs) as a measure of recent thymic emigrant cells in peripheral blood lymphocytes of 50 HIV-infected infants and children who were followed-up for 40 months after the start or change of antiretroviral therapy. At baseline, patients exhibited fewer TRECs than did uninfected control subjects. The increase in TRECs after antiretroviral therapy was greater in infants than in older HIV-infected children. Of interest, patients who demonstrated discordant responses (i.e., increased CD4 T cell counts without significant virologic suppression) also had substantial gains in TRECs. Furthermore, TRECs correlated positively with the number of CD4 and naive T cells and negatively with age and virus load. Measurement of TRECs may serve as a useful tool for evaluating immune reconstitution in HIV-infected children receiving antiretroviral therapy.     

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA(+) naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4(+) and CD8(+) cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.     

Changes in T cell receptor excision DNA circle (TREC) levels in HIV type 1-infected subjects pre- and post-highly active antiretroviral therapy

The T cell receptor excision DNA circle (TREC) level is an independent predictor of HIV-1 disease prognosis. We studied the temporal changes in TREC levels prior to and after highly active antiretroviral therapy (HAART) in a cohort of 131 Greek men with hemophilia who were followed up for up to 20 years since seroconversion (SC). TREC levels were determined in all available cryopreserved samples of peripheral blood mononuclear cells (PBMCs) using a multiplex real-time polymerase chain reaction (PCR) assay. Trends in log(10) TREC values were described using random effects models. Prior to HAART initiation TREC levels tended to decrease over time (mean rate of drop 19% per year; 95% CI: 16-22%). Initial TREC values were higher with younger age at SC, but the subsequent rate of drop did not differ significantly by age at SC. There was a monotonic relationship between baseline HIV-RNA levels and TREC slopes with steeper slopes at higher levels of HIV-RNA. The TREC slopes differed significantly by clinical outcome being steeper in subjects who progressed to AIDS sooner. After HAART initiation, TREC values tended to increase on average by 35% per year (95% CI: -7-94%) but the increase was evident only in subjects with a pre-HAART CD4 count below 80 cells/microl. TREC values, which likely represent a simple indicator of naive T-lymphocyte reserve, may be a clinically useful marker for long-term prognosis of HIV-1 infection and for immune reconstitution after successful HAART.     

Characterizing immune reconstitution after long-term highly active antiretroviral therapy in pediatric AIDS

In this study, we sought to characterize the T lymphocyte recovery in vertically HIV-1-infected children who respond to long-term highly active antiretroviral therapy (HAART). A 3-year longitudinal retrospective study was used to perform a cross-sectional study of 32 children rated according to the time course of CD4(+) T cell percentages in response to antiretroviral therapy and CDC clinical classification: (1) long-term asymptomatic (LTA group): 8 children in A1 during the whole follow-up period; (2) responsive to HAART (Rec group): 13 children in C3 before HAART who achieved CD4(+) T cell counts of > 500 cells/mm(3) after 3 years of HAART; and (3) nonresponsive to HAART (Non-Rec group): 11 children in C3 during the whole follow-up period despite 3 years of HAART. We also studied 17 healthy age-matched uninfected children as controls. Lymphoproliferative responses (LPRs) were evaluated by incorporation of [(3)H]thymidine, identification of T cell subsets by three-color flow cytometry, and determination of thymic production of T cells by quantification of T cell receptor rearrangement excision circles (TRECs). Interestingly, the Rec group showed an increase in percentage of CD4(+) T cells and a decrease in viral load, and recovered LPRs to mitogens and recall antigens, with values similar to those of the LTA group. Moreover, the Rec group produced similar percentages and absolute counts of naive (CD45RA(+)CD62L(+)) CD4(+) and CD8(+) T cells, and TRECs similar to those of the LTA group. In particular, the Rec group produced similar percentages of CD8(+)CD28(-)CD57(+) and CD8(+)CD28(-)CD57(-) T cell subsets compared with controls. Our data indicate that among children who have already progressed to AIDS and severe immunodeficiency but who respond to HAART, the immune system can recover and resemble those of nonprogressors or even uninfected children, in quantitative as well as in functional terms.     

Reduced CD127 expression on peripheral CD4+ T cells impairs immunological recovery in course of suppressive highly active antiretroviral therapy

Inefficient immune recovery under highly active antiretroviral therapy (HAART) represents a clinical issue. Twenty-seven of 121 HIV+ na?ve patients became immunological nonresponders (INRs) and 55 introduced therapy late [very late treated (VLT)]. INR displayed older age, lower CD4(+) cell counts, down-regulation of CD127(+)CD4(+) and higher apoptotic CD95(+)CD8(+). VLT also showed higher activated CD38(+)CD8(+)%. The only factor associated with INR status was CD127(+)CD4(+)%. INR showed lower baseline interleukin (IL)-7 levels and a reduced expression of IL-7R (CD127(+)) on na?ve and memory T-cells, reaching significance in memory CD127(+)CD45(+)R0(+)CD4(+). These results suggest a possible role for the IL-7/IL-7R system in the pathogenesis of poor immunological recovery during HAART.