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Session 44 Poster Presentations Lymphocyte Dynamics Session Day and Time: Wednesday 1:30 - 3:30 pm Room: Hall D

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Decreased Immune Activation Drives Naïve 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. Kovacs^1
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 naïve 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 naïve (CD45RO-/CD27⁺) and memory (RO⁺/27⁺, recall; RO⁺27^-, effector) subsets; and 3) TRECs (per million naïve 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 naïve 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. naïve CD4 cells (p = 0.04), but decreased to baseline (102,691) at 18 mos. The increase in naïve CD4 cell number between mos 0 and 18 correlated significantly with the baseline naïve 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 naïve cells or TREC/ul of blood. The pre-HAART to 18 mos change of TREC/mil naïve 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/µl noted between mos 6 and 18 correlated with the increase of naïve 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 naïve CD4 cells depends on decreased proliferation of CD4 T-cells as well as the baseline naïve 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.

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