Session 44Poster Presentations Lymphocyte Dynamics Session Day and Time: Wednesday 1:30 - 3:30 pm Room: Hall D
330 Decreased Immune Activation Drives Na´ve CD4 T-cell Reconstitution after HAART L. T. Matthews*1, I. Sereti1, V. Natarajan2, E. Jones3, C. Chow3, K. Yoder1, J. A. Metcalf1, H. C. Lane1, M. A. Polis1, J. A. Kovacs1 1Natl Inst of Allergy and Infectious Diseases, NIH, Bethesda, MD; 2Sci Applications Intl Corp, Frederick, MD; and 3Natl Inst of Hlth, Bethesda, MD
Background: HAART therapy leads to substantial reconstitution of HIV induced CD4 lymphopenia and the associated preferential decreases in na´ve CD4 populations. However, the contribution of thymic output vs enhanced survival and cell redistribution to this reconstitution are unclear.
Methods: Nineteen (19) HIV-1 infected patients (median age, 37 yrs) with a median baseline CD4 count of 282 cells/uL (range: 6-687) and median viral load of 55,029 copies/mL (range: 4,504-1,602,790) were studied prospectively before and after a median of 6 and 18 mos on HAART with 1) thymic CT (scored on a 0-5 scale); 2) T-cell immunophenotyping and intracellular Ki67 staining in na´ve (CD45RO-/CD27+) and memory (RO+/27+, recall; RO+27-, effector) subsets; and 3) TRECs (per million na´ve cells) in bead-separated CD4 and CD8 T-cells. Non-parametric tests were used for statistical analysis.
Results: Median CD4 count increased to 393 at 6 mos (p < 0.0001) and to 518 at 18 mos. (p = 0.02). The median total na´ve CD4 cells increased from 47 to 113 at 6 mos (p < 0.0001) and to 151 at 18 mos. (p = 0.001). No statistically significant changes were noted in thymic CT scores at 6 or 18 mos after HAART. At 6 mos, TRECs increased from 102,673-148,555/mil. na´ve CD4 cells (p = 0.04), but decreased to baseline (102,691) at 18 mos. The increase in na´ve CD4 cell number between mos 0 and 18 correlated significantly with the baseline na´ve CD4 cell number (R = 0.65, p = 0.02) and inversely with the baseline log of CD4+/Ki67+ counts (R = -0.52, p = 0.05) but did not correlate with the change in CD4 TREC/mil na´ve cells or TREC/ul of blood. The pre-HAART to 18 mos change of TREC/mil na´ve CD4 cells correlated with the decrease in the number of Ki67+ CD4 cells (R = 0.52, p = 0.07). CD4 TREC/ul blood increased from 7.2 pre-therapy to 11.4 at mos 6 and 17.3 at mo 18. The increase in CD4 TREC/Ál noted between mos 6 and 18 correlated with the increase of na´ve CD4 counts (R = 0.57, p = 0.02) and with the continuing decrease of Ki67+ CD4 effectors (R = 0.56, p = 0.03).
Conclusion: These data suggest that reconstitution of na´ve CD4 cells depends on decreased proliferation of CD4 T-cells as well as the baseline na´ve CD4 count. The absence of an increase in thymic tissue suggests that the increase in CD4 TREC/ul likely results from a decrease in CD4 cell turnover in the setting of stable thymic output.