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CD4+ gains in HIV patients on HAART result from release of T cells recently migrated from the thymus, redistribution from lymphoid tissues, proliferation in the periphery and/or reduced apoptosis. The relative contribution of each mechanism in CD4 restoration in patients with suppressed viremia switching antiretrovirals is unclear.HIV patients with undetectable viremia on HAART were identified at our clinic. A subset switched to raltegravir was compared with another group that kept therapy unmodified. Naive and memory CD4+ T-cells were measured by flow cytometry using CD45RA and CD27, respectively. Activation was examined using CD38 and recent thymic emigrants using CD31. Apoptosis was analyzed measuring soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL).Thirty-seven patients were examined, 19 switched to raltegravir and 18 controls, after a median of 26 months of suppressed viremia. At 6 months, mean CD4 cell counts significantly increased in raltegravir patients from 322 to 448 cells/μl (P = 0.026) but not in controls (from 312 to 330 cells/μl; P = 0.813). No significant changes were recognized in activation or CD31 expression in any group. In raltegravir patients, however, the proportion of naive CD4+ T cells significantly increased (P = 0.014) as well as CD38 expression in these cells (P = 0.036). A positive correlation was found between CD38 and CD31 expression in naive CD4+ T cells (R2 = 0.51, P < 0.001). TRAIL and FasL did not decline significantly in any group.HIV patients with prolonged undetectable viremia on HAART experience more pronounced CD4 gains after raltegravir switching than keeping the same regimen. An increased production of naive CD4+ T cells largely explains this effect.