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

Abstract

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...

Supranormal thymic output up to 2 decades after HIV-1 infection

“…[5-7] Our detailed analysis of TCR repertoire substantiates and extends prior studies of HIV-1-infected adults in whom ART does not generally restore CD4 + T-cell numbers to normal or fully normalize skewing of the TCR repertoire, as assessed by various tools ranging from relatively indirect to more precise measures of diversity such as CDR3 size distributions (“spectratyping” or “immunoscoping”), DNA hybridization kinetics (“Amplicot”), multiplex amplification of V-J segments, and CDR3 sequencing,[8, 23, 47-50] and one study in children/adolescents indicating that perturbations in TCR diversity of naïve cells begin to resolve within several months of therapy. [19] Because HIV-1 infection is typically associated with disrupted thymic architecture, involution of the thymic cortical epithelial space, and fibrosis of the peripheral lymph nodes that are required for expansion of thymic emigrants,[41, 51-53] the novel finding of substantially increased TCR breadth in the recent thymic emigrant CD4 + T-cell compartment of our HIV-1-infected subjects was surprising. Supporting this observation, recent trials of administering recombinant human IL-7 to infected persons on ART have demonstrated enhanced naïve CD4 + T-cell production accompanied by indirect measures of increased TCR diversity.…”

“…[18] Others have demonstrated that T-cell receptor CDR3 distribution perturbations are rapidly reduced in some children and adolescents during ART [19] suggesting that some degree of normalization of the TCR repertoire is possible. However, these measurements have not excluded qualitative abnormalities in thymopoiesis that might result from the known impact of HIV-1 on the architecture of both the thymus and secondary lymphoid tissues.…”

The γδ T-cell receptor repertoire is reconstituted in HIV patients after prolonged antiretroviral therapy

“…Studies on TCR recombination excisional circles (TRECs), a byproduct of TCR rearrangement [26], and phenotypically defined recent thymic emigrants [27] supported thymic output as the driver of immune reconstitution. Using spectratyping methods, the TCR Vβ repertoire complexity was increasing during reconstitution [28] although spectra-type data are not corrected for sample size effects which can be especially important for low CD4 + cell counts, and expansion of individual clones can skew the spectratype and confuse interpretation of data. Sequencing studies are needed to confirm whether reconstitution is associated with increasing TCR repertoire complexity due to new cell synthesis.…”

Perspectives for immunotherapy: which applications might achieve an HIV functional cure?

“…However, if the rise in the CD4 count results mainly from CD4 + T-cell proliferation and survival, the repertoire will remain uncompleted, even though the total number of CD4 + T-cells has normalized [41–43]. …”