The Distribution and Immune Profile of T Cell Subsets in HIV-Infected Children from Uganda

Abstract

T cell activation is an important mechanism in HIV-associated immune depletion. We have previously demonstrated an association between the hyperactivation of CD4(+) and CD8(+) T cells and low CD4 status in HIV-infected Ugandan children. In this study, we explore differences in activation between naive and memory T cells in HIV-infected Ugandan children. A significant correlation between CD4- and CD8-mediated immune activation and CD4 status was observed only in the memory T cells. Antiretroviral (ART) untreated and treated HIV-positive and HIV-negative children displayed similar profiles of activation and distribution within the CD4(+) naive T cells. In contrast, significantly higher immune activation of the memory CD4(+) T cell subset was seen in ART-untreated children when compared to ART-treated or HIV-negative children. ART-mediated viral suppression led to the correction of CD4(+) immune activation to levels seen in uninfected children but did not increase the size of the memory CD4(+) T cell population. High levels of CD8(+) immune activation were also found in both naive and memory cell subsets. Antiretroviral treatment led to the normalization of CD8(+) T cell activation but did not correct the distribution of naive CD8(+) T cells. We also assessed PD-1 expression on CD8(+) T cells as a measure of immune dysfunction. Upregulation of PD-1 was highest in untreated children but persisted in ART-treated children compared to uninfected children. The mechanisms of immunopathogenesis in pediatric HIV infection likely involve distinct contributions from individual naive and memory T cells subsets.

CD8+ T-cell reconstitution in recipients of umbilical cord blood transplantation and characteristics associated with leukemic relapse

“…The frequencies of PD-1-expressing CD8 ϩ T cells and CD4 ϩ T cells at 3 months after UCBT were also significantly higher than those observed in healthy adults and healthy children (P Ͻ .0001), consistent with recent reports. 29,30 Frequencies of PD-1 ϩ CD8 ϩ T cells were inversely correlated with CD8 ϩ and CD4 ϩ T-cell counts (P ϭ .0077, r ϭ Ϫ0.4124, and P ϭ .0052, r ϭ Ϫ0.4338, respectively), which highlights the association between lymphopenia and impaired CD8 ϩ T-cell function in the first months after UCBT ( Figure 5C-D). Overall, median frequencies of PD-1 ϩ T cells were higher in the CD4 ϩ than in the CD8 ϩ T-cell compartment (P ϭ .0039), and the frequency of PD-1 ϩ CD8 ϩ T cells was correlated with the frequency of PD-1 ϩ CD4 ϩ T cells throughout the follow-up period (P Ͻ .0001, r ϭ 0.7665; supplemental Figure 5B-C).…”

“…In recent years, several groups have examined the reconstitution of T cells specific for CMV 32 or for leukemia-associated antigens such as PR1 33 and WT1. 34 In contrast, the present study was largely focused on the repertoire of T cells that recognize the Melan-A [26][27][28][29][30][31][32][33][34][35] A27L peptide in the context of HLA-A2 (A2/Melan-A), because these cells represent one of the only preimmune T-cell repertoires that can be studied in humans, particularly when the number of cells that can be obtained from study subjects is limited. 15,17,18 Consistent with these previous reports, clonally diversified A2/Melan-A ϩ CD8 ϩ T cells were reproducibly detected in UCB graft inoculums.…”

“…Tetramer-sorted microcultures (2 ϫ 10 5 cells) were incubated with APCconjugated anti-CD107a mAb (H4A3; BD Biosciences) and 221.A2 cells in the presence of 10 g/mL Melan-A [26][27][28][29][30][31][32][33][34][35] A27L peptide at 37°C in RPMI 1640 medium supplemented with 10% vol/vol FBS. Culture medium alone was used as negative control.…”

“…(5) How does their polyfunctionality, which reflects their efficacy to control chronic viral infections, 16 evolve in the post-UCBT period? We examined CD8 ϩ T cells specific for the HLA-A2-restricted Melan-A [26][27][28][29][30][31][32][33][34][35] A27L peptide (A2/Melan-A) 17 as a model for the reconstitution of an antigen-specific repertoire. A2/Melan-A-specific T cells represent one of the only preimmune T-cell repertoires that can be studied in humans.…”

Changes in Cellular Immune Activation and Memory T-Cell Subsets in HIV-Infected Zambian Children Receiving HAART

“…10 However, only two studies specifically examined central memory CD4 + T cells among children born to HIV-infected mothers, both of which used cross-sectional study designs. 11;12 In the few studies measuring T cell subsets before and after HAART initiation in HIV-infected children in sub-Saharan Africa, T cell activation was assessed 6;13;14 but changes in T cell subset compositions are largely unknown. To better understand the impact of HAART on T cell composition in HIV-infected children residing in sub-Saharan Africa, particularly activated and memory phenotypes, we measured circulating CD4 + and CD8 + T cell populations in HIV-infected Zambian children before and at 3-month intervals after HAART initiation and compared to levels in control children.…”