CD4<sup>+</sup>and CD8<sup>+</sup>T Cell Receptor Repertoire Perturbations with Normal Levels of T Cell Receptor Excision Circles in HIV-Infected, Therapy-Naive Adolescents

Pahwa, Savita; Chitnis, Vivek; Mitchell, Richard M.; Fernandez, Sanjit; Chandrasekharan, Alamelu; Wilson, Craig M.; Douglas, Steven D.

doi:10.1089/088922203766774531

Cited by 19 publications

(15 citation statements)

References 22 publications

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“…However, the cohort selected for study had relatively normal total CD4 T-cell counts (range, 432 to 911 cells/l), and in general, the individuals in that cohort were asymptomatic. We and others have shown that many HIV-infected children and adolescents have intact thymic output and normal proportions of naïve T cells, as measured by the levels of TRECs and expression naïve T-cell surface markers (20,33,51). A novel finding in this study is the elevated level of perturbations within the CD4 and CD8 CD45RA subsets prior to the CD4 T-cell decline.…”

Section: Discussionmentioning

confidence: 50%

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Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Yin¹,

Kou²,

Rodriguez

et al. 2009

Clin Vaccine Immunol

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Human immunodeficiency virus (HIV) type 1 infection perturbs the T-cell receptor (TCR) V␤ repertoire.The TCR CDR3 length diversity of individual V␤ families was examined within CD45RA and CD45RO CD4 T cells to assess the impact of the virus on clonality throughout CD4 T-cell activation and differentiation. A cross-sectional and longitudinal cohort study of 13 HIV-infected and 8 age-matched healthy children and adolescents examined the V␤ CDR3 length profiles within CD4 T-cell subsets by the use of spectratyping. HIV-infected subjects demonstrated higher numbers of perturbations in CD4 CD45RA T cells (5.8 ؎ 4.9 V␤ families) than healthy individuals (1.6 ؎ 1.8 V␤ families) (P ‫؍‬ 0.04). Surprisingly, CD4 CD45RO central memory T cells from infected subjects showed no increased perturbations compared to the perturbations for the same cells from healthy subjects (2.9 ؎ 3.1 and 1.1 ؎ 1.8 V␤ families, respectively; P ‫؍‬ 0.11). CD4 CD45RA TCR perturbations were higher among infected subjects with >25% CD4 cells than healthy subjects (mean number of perturbed V␤ families, 6.6 ؎ 5.4; P ‫؍‬ 0.04). No correlations between perturbations in CD4 subsets and pretherapy age or viral load were evident. In contrast to CD8 T cells, HIV induces TCR disruptions within CD45RA but not CD45RO CD4 T cells. Therapy-induced viral suppression resulted in increases in thymic output and the normalization of the diversity of TCR within CD45RA CD4 T cells after 2 months of treatment. Perturbations occur prior to CD4 T-cell attrition and normalize with effective antiretroviral therapy. The impact of HIV on the diversity of TCR within naïve, central memory, and effector memory CD4 T cells is distinctly different from that in CD8 T cells.Human immunodeficiency virus type 1 (HIV-1) infection alters T-cell homeostasis by both impairing thymic output and inducing chronic T-cell activation. These disruptions are manifest by the increased level of expression of T-cell activation markers and decreased numbers of naïve T cells from the thymus (10,12,51). Oligoclonal T-cell expansion results in perturbations of the T-cell receptor (TCR) V␤ repertoire within both CD4 and CD8 T cells, with CD8 T cells being affected to a greater extent than CD4 T cells (7,12,16,29,50). Many of these abnormalities occur prior to CD4 T-cell attrition and are not fully reconstituted when viral replication is controlled by antiretroviral therapy (6, 17, 30). Multiple mechanisms have been postulated to contribute to this processes of aberrant T-cell activation and clonal expansion, including microbial translocation across the gastrointestinal tract as a result of virus-induced intestinal fibrosis (4,5,40) and the loss of immune regulation due to chronic HIV-induced antigenemia (8,22).CD4 and CD8 T cells are heterogeneous populations that differ functionally and in their expression of activation and differentiation markers, forming the basis of their classification as naïve, central memory (CM), or effector memory (EM) T cells (42). Isoforms of CD45 (CD45RA and CD45RO) are frequ...

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Section: Discussionmentioning

confidence: 50%

“…Overall, the TCR V␤ repertoire is less perturbed in CD4 T cells than in CD8 T cells in healthy children and adolescents (16,18,33,47). Our results show that in healthy children, CD8 T-cell perturbations are primarily the result of oligoclonal expansions within CD8 CD45RO T cells (26).…”

Section: Discussionmentioning

confidence: 67%

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Yin¹,

Kou²,

Rodriguez

et al. 2009

Clin Vaccine Immunol

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“…HIV-infected treatment-naive adolescents have been shown to harbor greater perturbations in their TCR V␤ repertoire in comparison with HIV-negative subjects, and these were negatively associated with CD4 TREC levels (49). Different abilities in maintaining a diverse T cell repertoire between LTSNPs and TPs might explain the persistence of good HIV-1-specific CD4 ϩ T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children

Chakraborty

A-S.

Sutton

et al. 2005

The Journal of Immunology

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Without treatment most HIV-1-infected children in Africa die before their third birthday (>89%) and long-term nonprogressors are rare. The mechanisms underlying nonprogression in HIV-1-infected children are not well understood. In the present study, we examined potential correlates of delayed HIV disease progression in 51 HIV-1-infected African children. Children were assigned to progression subgroups based on clinical characterization. HIV-1-specific immune responses were studied using a combination of ELISPOT assays, tetramer staining, and FACS analysis to characterize the magnitude, specificity, and functional phenotype of HIV-1-specific CD8+ and CD4+ T cells. Host genetic factors were examined by genotyping with sequence-specific primers. HIV-1 nef gene sequences from infecting isolates from the children were examined for potential attenuating deletions. Thymic output was measured by T cell rearrangement excision circle assays. HIV-1-specific CD8+ T cell responses were detected in all progression groups. The most striking attribute of long-term survivor nonprogressors was the detection of HIV-1-specific CD4+ Th responses in this group at a magnitude substantially greater than previously observed in adult long-term nonprogressors. Although long-term survivor nonprogressors had a significantly higher percentage of CD45RA+CD4+ T cells, nonprogression was not associated with higher thymic output. No protective genotypes for known coreceptor polymorphisms or large sequence deletions in the nef gene associated with delayed disease progression were identified. In the absence of host genotypes and attenuating mutations in HIV-1 nef, long-term surviving children generated strong CD4+ T cell responses to HIV-1. As HIV-1-specific helper cells support anti-HIV-1 effector responses in active disease, their presence may be important in delaying disease progression.

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“…34 No decreased CD4 TREC contents have been found in HIV-1-infected adolescents compared with HIV-negative adolescents. 35 Furthermore, studies in simian immunodeficiency virus (SIV)-infected monkeys with no signs of AIDS have shown increased numbers of mature thymocytes and increased cell proliferation in the thymus. 36 Thymocyte numbers were severely reduced only in SIV-infected monkeys with clinical signs of AIDS.…”

Section: Discussionmentioning

confidence: 99%

“…The slight differences in age among the different groups were not statistically significant (P Ͼ .05). Most age groups (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), and 40-49 years) contained a similar number of subjects (approximately 70-75), but the number was lower (n ϭ 33) in the 50-to 59-yearold group. As a control group, 120 randomly selected, healthy, HIV-negative blood donors were recruited.…”

Section: Study Groupsmentioning

confidence: 99%

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

Nobile¹

2004

Blood

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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

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CD4⁺and CD8⁺T Cell Receptor Repertoire Perturbations with Normal Levels of T Cell Receptor Excision Circles in HIV-Infected, Therapy-Naive Adolescents

Cited by 19 publications

References 22 publications

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children

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

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CD4+and CD8+T Cell Receptor Repertoire Perturbations with Normal Levels of T Cell Receptor Excision Circles in HIV-Infected, Therapy-Naive Adolescents

Cited by 19 publications

References 22 publications

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children

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

Contact Info

Product

Resources

About

CD4⁺and CD8⁺T Cell Receptor Repertoire Perturbations with Normal Levels of T Cell Receptor Excision Circles in HIV-Infected, Therapy-Naive Adolescents