878 Relationship between Cell-associated HIV-1 DNA and Thymic Output in HIV-1 Infected Children on Antiretroviral Therapy in the PENTA 5 Trial A. De Rossi*1, D. M. Gibb2, D. De Forni1, S. Walker2 1Univ of Padova, Italy and 2Med Res Council, London, UK
Background: Patients (pts) on ART have increases in CD4+ lymphocytes but persisting cell-associated HIV-1 DNA, even when HIV-1 RNA levels are undetectable. As thymic output is crucial to immune reconstitution in children on ART, we evaluated the relationship between HIV-1 DNA dynamics and thymic output.
Methods: Cell-associated HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC), a measure of thymic output, were quantified in PBMC in 33 HIV-1 infected ART-naive children at baseline, and 4, 12, 24, 48, and 96 wks after ART initiation (median age 7.1 yrs (range 0.3-15.5), CD4% 17%, HIV-1 RNA 5.0 log10 c/ml). Quantification was performed by real-time PCR; copy numbers were normalized to the number of ß-actin genes, and expressed relative to 106 PBMC (2x106 ß-actin copies) and per ml (attributing HIV-1 DNA load to the CD4 cell fraction). Longitudinal mixed models were used to assess the effects of baseline levels and age, and changes in CD4 and HIV-1 RNA on TREC and HIV-1 DNA response.
Results: At baseline, log10 TREC was positively associated with CD4% and HIV-1 DNA, and inversely associated with age and HIV-1 RNA (p < 0.05). In contrast, baseline HIV-1 DNA only depended on TREC, e.g., 0.80 log10 higher HIV-1 DNA per ml for every log10 higher TREC per ml (p = 0.001); age, CD4% and HIV-1 RNA were not independent predictors (p > 0.5). Overall, there were significant decreases in HIV-1 DNA and increases in TREC in PBMC, and per ml after ART initiation (p < 0.0001). However, decreases in HIV-1 DNA were smallest when increases in TREC were largest (p = 0.002). There was no association between changes in HIV-1 DNA and changes in CD4% or HIV-1 RNA (p > 0.4). The relationship between changes in HIV-1 DNA and TREC varied according to the phase of HIV-1 RNA decline (p = 0.14). Among children with stable HIV-1 RNA < 50 c/ml after initial HIV-1 RNA decline there was a smaller increase in HIV-1 DNA for every 1 log10 greater increase in TREC per ml (0.20 log10 copies per ml, p = 0.11), compared with children who never achieved HIV-1 RNA < 50 c/ml (0.36, p = 0.01) and children who achieved HIV-1 RNA < 50 c/ml but had 2 or more blips (0.78, p = 0.01).
Conclusions: These data suggest that overall declines in HIV-1 DNA are slowest in children with greatest increases in TREC, implying ongoing infection of naive cells. However, in children with stable HIV-1 RNA < 50 c/ml, in whom TREC increases are also smaller, the infection of naive cells is occurring at a slower rate.