Proposed experiments test the hypothesis that continued replication, as marked by shortened telomeres, results in clonal exhaustion and leads to declining pCTL frequencies. Experiments will confirm that HIV-infected children have evidence of increased CD8+ cell turnover by measuring telomere lengths in their CD8+CD28- cells. Expanded clonal CD8+ subsets expressing a particular Vbeta will be isolated for direct telomere length measurements. Longitudinal changes in the telomere length of the expanded subsets will be determined using cryo-preserved PBMC collected from children over the past 5 years. Clonality, surface marker phenotype, and ability to mediate CTL activity will be determined for these expanded subsets. Particular HIV-1 specific CTL will be generated from longitudinally stored samples and their telomere lengths will be compared in serial samples. As a control EBV-specific CTL will be similarly studied. The frequency of the clone in PBMC will be determine by sequence analysis of the TCR junctional regions. Changes in telomere length and the frequency of particular clones will be compared before and after therapy in children starting high active anti-retroviral drugs. This investigation will lead to greater understanding of the mechanisms leading to decline in developing treatment strategies and determining the capacity for immune restoration.
| McFarland, Elizabeth J; Harding, Paul A; Striebich, Christopher C et al. (2002) Clonal CD8+ T cell expansions in peripheral blood from human immunodeficiency virus type 1-infected children. J Infect Dis 186:477-85 |
| McFarland, E (1999) Immunizations for the immunocompromised child. Pediatr Ann 28:487-96 |
