Evaluation of T Cell Receptor Gene Rearrangement Excision Circles after Antiretroviral Therapy in Children Infected with Human Immunodeficiency Virus

Chavan, Surendra; Bennuri, Bindu; Kharbanda, Monica; Chandrasekaran, Alamelu; Bakshi, Saroj; Pahwa, Savita

doi:10.1086/320197

Cited by 52 publications

(51 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these studies concerning immune reconstitution during HAART, a selection was made for immunological responders and/or nonresponders (8, 10 -12, 16, 25, 27, 44, 45), age-matched controls were not included (5, 7, 10, 11, 25, 27, 46 -48), and mainly relatively short-term effects were studied (5-7, 10, 19, 47-50). In many of the pediatric studies, patients had been pretreated (5,6,12,24,25,48,49) and residual viral load often persisted (7,11,12,24,25,48).…”

Section: Discussionmentioning

confidence: 99%

Restoration of the CD4 T Cell Compartment after Long-Term Highly Active Antiretroviral Therapy without Phenotypical Signs of Accelerated Immunological Aging

Vrisekoop

Gent

Boer

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/μl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4–9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/μl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.

show abstract

Section: Discussionmentioning

confidence: 99%

Restoration of the CD4 T Cell Compartment after Long-Term Highly Active Antiretroviral Therapy without Phenotypical Signs of Accelerated Immunological Aging

Vrisekoop

Gent

Boer

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Data suggest that TREC levels change during aging and disease (9,10,13,14,15,17,24,41). However, it is still an open question as to whether TREC concentrations are mainly affected by thymic output or peripheral T cell events.…”

Section: Discussionmentioning

confidence: 99%

“…Recent clinical data support the thymus as a key contributor to TREC concentration decline during aging and HIV-1 infection (38,41). One study suggests that changes in peripheral T cell division do not adequately explain many observations of TREC concentrations, including similar ratios of CD4…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants

Kirschner

2002

The Journal of Immunology

125

View full text Add to dashboard Cite

The human thymus exports newly generated T cells to the periphery. As no markers have been identified for these recent thymic emigrants (RTE), it is presently impossible to measure human thymic output. T cell receptor excision circles (TREC) have been recently used to assess thymic output during both health and disease. Using a mathematical model, we quantify age-dependent changes both in the number of RTE generated per day and in TREC concentration during an 80-year lifespan. Through analyses, we demonstrate that RTE and peripheral T cell division have the same potential to affect TREC concentration at any age in healthy people. T cell death also influences TREC concentration, but to a lesser extent. During aging, our results indicate that thymic involution primarily induces an age-dependent decline in TREC concentrations within both CD4+ and CD8+ T cell populations. We further apply this model for studying TREC concentration during HIV-1 infection. Our analyses reveal that a decrease in thymic output is the major contributor to the decline in TREC concentration within CD4+ T cells, whereas both increased peripheral T cell division and decreased thymic output induce the decline in TREC concentration within CD8+ T cells. Therefore, we suggest that T cell turnover should be examined together with TREC concentration as a measure of RTE. If peripheral T cell division remains relatively unchanged, then TREC concentration indeed reflects thymic output.

show abstract

“…A number of studies have shown that TREC levels decline with HIV infection and increase after treatment with highly active antiretroviral therapy, suggesting that changes in viral replication can lead also to changes in levels of TRECs (8,9,(23)(24)(25). Recent data suggest that the decline in TREC levels in HIV patients may be caused by increased cell division associated with immune activation by HIV rather than a decrease in thymic function (11,26).…”

Section: Discussionmentioning

confidence: 99%

Increased peripheral expansion of naive CD4+ T cellsin vivoafter IL-2 treatment of patients with HIV infection

Natarajan

Lempicki

Sereti

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Intermittent interleukin-2 (IL-2) therapy has been shown to increase the number of CD4؉ T cells, preferentially cells with a naive phenotype, in patients with HIV infection. For this report we investigated the mechanism underlying this expansion by studying the relative roles of peripheral expansion and thymic output. In a cohort of six patients receiving IL-2 over a period of 1 year, the mean number of naive CD4؉ T cells increased from 139 to 387 cells per l while levels of T cell receptor rearrangement excision circles (TRECs) declined from 47,946 to 26,510 copies per 10 6 naive T cells, thus making it unlikely that the CD4؉ T cell count increases were secondary to increase in thymic output. To examine directly the impact of IL-2 on peripheral expansion, peripheral blood mature, naive CD4؉ T cells were labeled ex vivo with 5-bromodeoxyuridine as well as stained directly for Ki67. These studies revealed a 7-fold increase in the percentage of 5-bromodeoxyuridine-positive cells and a 20 -40-fold increase in Ki67 staining in the naive CD4؉ T cell pool in the setting of IL-2 administration. This degree of increase in mature CD4؉ T cell turnover induced by IL-2 does not compromise the future replicative potential of these cells, because longitudinal measurements of telomere length went from 6,981 to 7,153 bp after 1 year of IL-2 therapy. These data strongly suggest that much of the increase in CD4؉ cells associated with IL-2 treatment is caused by peripheral expansion of existing naive CD4؉ T cells rather than increased thymic output and that these increases occur without compromising the potential of these cells for further cell division.

show abstract

Evaluation of T Cell Receptor Gene Rearrangement Excision Circles after Antiretroviral Therapy in Children Infected with Human Immunodeficiency Virus

Cited by 52 publications

References 51 publications

Restoration of the CD4 T Cell Compartment after Long-Term Highly Active Antiretroviral Therapy without Phenotypical Signs of Accelerated Immunological Aging

Restoration of the CD4 T Cell Compartment after Long-Term Highly Active Antiretroviral Therapy without Phenotypical Signs of Accelerated Immunological Aging

Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants

Increased peripheral expansion of naive CD4+ T cellsin vivoafter IL-2 treatment of patients with HIV infection

Contact Info

Product

Resources

About