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Combination Antiretroviral Therapy Corrects the Disruptions in the TCR Vbeta Repertoire within CD45RA CD8 T Cells of HIV-Infected Children
Z. C. Kou*, J. S. Puhr, M. Goodenow, and J. Sleasman
Univ. of Florida, Gainesville
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Background: HIV-1 infection disrupts thymic output and skews normal maturation of CD8 T cells in infected children. Infection also results in alterations within the TCR repertoire. Control of viral replication through HAART should reverse these virus-induced abnormalities and restore TCR diversity.
Methods: Using TCR spectra-typing, 16 HIV-infected infants and children were examined prospectively to evaluate HIV-induced changes in the TCR repertoire in CD45RO and CD45RA CD8 T cells before, and after, HAART. The results were compared to 10 healthy age-matched control subjects.
Results: CDR3 length diversity within Vbeta families from healthy children showed a predominantly Gaussian distribution in both CD45RA and CD45RO CD8 T cells. A 3- to 4-fold higher incidence of TCR perturbations and oligoclonal expansion in HIV-infected children was observed prior to therapy (p< 0.001 Student's t test for both subsets). The CD8 CD45RA T cells expressed high levels of CD11a and low expression of CD27 indicating that the expanded cells were activated, antigen-primed, effector T cells. High pre-therapy viral load and more advanced immune suppression correlated with a greater degree of TCR perturbations within CD45RA, but not CD45RO CD8 T cells (p< 0.01 Spearman linear regression analysis). Following 8 weeks of treatment and effective control of viral replication normal, Gaussian CDR3 length distribution was reestablished and expression of CD11a decreased in the CD45RA CD8 T cells.
Conclusions: HIV-infected children lose normal TCR diversity within terminally differentiated CD45RA CD8 T cells but the defect can be corrected with effective therapy. Control of viral replication leads to the emergence of new CDR3 lengths and the re-establishment of a Gaussian CDR3 length distribution. Disruption of TCR diversity in CD45RA T cells is a contributing mechanism to HIV-induced T-cell anergy and loss of CD8 T-cell control of viral replication that can be corrected by HAART.
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