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Background:  HIV infection perturbs TCR Vb CDR3 length distributions in CD8 CD45RA and CD45RO T cells that are restored in the CD45RA subset with ART. This study examines the extent of TCR Vb perturbations in CD4 T-cell subsets in infected children before and after treatment.

Methods:  CDR3 length diversity within 21 Vb families was examined by spectratyping of CD45RA and CD45RO CD4 and CD8 T cells. A total of 13 infected children was examined prior to ART, including 6 individuals in whom both CD4 and CD8 subsets were evaluated in the same subject. A cohort of healthy, age-matched children was used for comparisons. The number of Vb families with perturbations per child (NP) defined the extent of TCR disruption. Mann-Whitney Rank Sum test tested statistical differences.

Results:  Vb families within CD4 T cells from healthy children displayed few perturbations with no differences in NP in CD45RA compared with CD45RO (p = 0.51). In healthy children, NP was higher in CD8 CD45RO T cells than CD4 CD45RO (p = 0.03) but these differences were not seen in CD45RA subsets (p = 0.86). HIV-infected children showed greater NP in CD4 CD45RA than healthy children (p = 0.03), but there was no difference when comparing CD45RO subsets (p = 0.09). In CD4 and CD8 T cells in the same individuals, NP was not different in CD45RA subsets (p = 0.49) but was higher in CD8 CD45RO T cells than in CD4 CD45RO T cells, (p = 0.002). After initial ART, 4 HIV-infected children were followed longitudinally. All optimally suppressed viral replication with median CD4 T cell increases of 236 cells/µL by 24 weeks. Within CD4 CD45RA T cells NP declined from a median of 13.5 to 5.5. In contrast, NP in CD4 CD45RO T cells increased during the initial 4 to 8 weeks on ART, correlating with rising CD4 CD45RO T cells of 141 cells/ µL. By 8 to 12 weeks on treatment, NP returned to low, pre-therapy levels. Analysis of individual CDR3 lengths demonstrated that, unlike what has been previously shown in CD8 T cells, individual CDR3 peaks did not persist.

Conclusions:  The TCR Vb T repertoire is not as disrupted in CD4 CD45RA and CD45RO T cells as it is in the CD8 subpopulations. Control of viral replication with ART results in a rapid return to Gaussian CDR3 distributions in CD4 CD45RA, but an increase in perturbations in CD4 CD45RO T cells. This paradoxical response is likely due to re-circulation of CD45RO cells from lymph nodes to peripheral blood following control of viral replication.

Keywords: T cell receptor repertoire; CD45RA and CD45RO; HIV-infected children