Session 14Oral Abstract Presentations Immune-Based Therapy Session Day and Time: Wednesday 10 - 11:15 am Presentation Time: 11:00 Room: Auditorium
63 Differential Modulation of Whole Blood Naïve and Memory CD4+ and CD8+ T-cell Subsets by Viral Replication During Therapy Interruption in Chronically HIV-1 Infected Patients E. Papasavvas*1, B.Thiel1, M. Pistilli1, A. Mackiewicz1, M. Farabaugh1, E. C. Moore1, C. Gallo2, R. Gross3, A. Foulkes3, K. Mounzer2, L. Schmidt2, J. Ondercin2, J. Shull2, J. R. Kostman2, L. J. Montaner1 1Wistar Inst, Philadelphia, PA; 2Philadelphia Field Initiating Group for HIV-1 Trials, PA; and 3Ctr for Clin Epidemiology and Biostatistics and the Div of Infectious Diseases, Univ of Pennsylvania, Philadelphia, PA
Background: The modulation of naïve and memory T-cell subsets during Therapy Interruptions (TIs) in chronically HIV-1 infected patients (pts) is undetermined.
Methods: An immunology sub-study of 41 chronically HIV-infected and stably suppressed pts enrolled in a randomized trial on the effects of TI characterized changes in CD4+ and CD8+ naïve and memory (central/effector) T-cell subsets before, during and after a 4-wk TI in study groups with 1 or 2 TIs. CD4 and CD8 T-cell subsets were defined in whole blood as naïve (CD45RA+/CD62L+), central memory (CD45RA-/CD62L+), total effector memory (CD62L-), effector intermediate (CD45RO+/CD45RA-/CD62L-) and effector terminal (CD45RA+/CD62L-) T-cells. Above listed whole blood subsets were also compared in cryopreserved PBMC against naive and memory subsets defined by CCR7 expression and their changes were compared to changes in HIV-specific IFN-gamma CD8 T-cell responses. Statistics were performed with JMP 4.
Results: A significant decrease of CD8 naïve (p < 0.05) and effector terminal cells (p < 0.05) and an increase of central memory cells (p < 0.05) were found by wk 4 of TI in all subjects. In addition, subjects with a prior history of a recent TI also showed a significant increase of CD8 effector (p < 0.05) and effector intermediate subsets (p < 0.05) by wk 4 of TI. Therapy re-initiation and subsequent return to viral load < 50 copies/ml resulted in a return of all changes back to baseline. Interestingly, in the CD4 subset, only a significant increase in the naïve subset was documented after TI and resuppression when comparing to levels at the onset of TI (p = 0.02). Parallel analysis of changes in the IFN-gamma producing CD8-cells against HIVp55 resembled changes in the CD8 effector intermediate memory. At wk 4 of TI there was a negative correlation between CD8 memory subsets (effector terminal vs central [rho = -0.57, p = 0.01] and effector intermediate [rho = -0.68, p = 0.001]). Surprisingly, central and effector intermediate subsets were positively correlated (rho = 0.76, p = 0.0002) suggesting a redistribution/expansion of central memory. Definition of the subsets by CCR7 expression confirmed similar subset changes.
Conclusion: The increase in circulating CD8 T-cell memory after TI is associated with an increase in both central and effector intermediate subsets while effector terminal subsets decrease. All documented changes in CD8+ T-cell subsets over a 4-wk TI were reversible following re-treatment and re-suppression (< 50 copies/ml).
