355 Immunologic Evidence that Start of ART can be Deferred for CD4 T-cell Count < 200/mul M. Nobile*, R. Correa, K. Ellefsen-Lavoie, E. Aschwanden, M. Spasojevic, C. D'Agostino, L. Codarri, M. Khonkarly, G. Pantaleo Lab of AIDS Immunopathogenesis, CHUV, Lausanne, Switzerland
Background: Recent studies have shown that ART is still effective in patients (pts) with CD4 T-cell counts down to 200 cells/µl in preventing the progression of HIV disease and in the recovery of CD4 T-cells, thus indicating that start of ART can be deferred for CD4 T-cell counts >200/µl. The immunologic mechanisms responsible for the recovery of CD4 T-cells are unclear.
Methods: Thymic output was measured by TREC levels and cell cycle genes by cDNA expression array in purified CD4 and CD8 T-cells. Analysis of TREC levels was performed in HIV-infected subjects stratified by the stage of HIV disease (early: > 500 CD4 T-cells/µl; intermediate: < 500 > 200; late: < 200) and by age (20 to 60 yrs, n = 259). As control group, we used 110 HIV- donors stratified by age (20-60 yrs). Cell cycle gene expression patterns in HIV-infected (n = 8) and HIV-negative subjects (n = 8) were assessed by cDNA expression array.
Results: TREC levels in CD8 T-cells were significantly lower in HIV-infected subjects at any stage of disease compared to the control group (p < 0.001). In contrast, TREC levels in CD4 T-cells were significantly higher in HIV-infected subjects (n=110; p = 0.002) at early stage disease while no significant differences were observed at intermediate stages of disease (n=106 ; p = 0.075), and were severely reduced only at late stages of disease (n = 48; p = 0.003). With regard to cell cycle genes, the expression of genes involved in the regulation of G1/S phase (Cyclin D3, E, CDK2 and 4, p53, mdm2) in CD8 T-cells of HIV-infected subjects was similar to that of in vitro stimulated CD8 T-cells of HIV-negative donors, thus indicating active cycling and activation of CD8 T-cells of HIV-infected subjects. With regard to CD4 T-cells of HIV-infected patients, there was no evidence for the up-regulation of CDK2 and 4, while there was an higher expression of p53 (responsible for cell cycle arrest and apoptosis) and lower expression of mdm2. These results are compatible with a cell cycle arrest and with an increased apoptosis.
Conclusions: These results indicate that thymic output becomes deficient only at late stage disease, and the increased/normal thymic output at early and intermediate stages of disease help to explain why recovery of CD4 T-cells can be achieved even if therapy is initiated in pts with CD4 T-cell counts as low as 200/µl.
