Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4 ؉ T cell counts > 350 cells͞l and viral load below the limits of detection for >1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies͞ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log 10 copies) day ؊1 , which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log 10 copies) day ؊1 (P ‫؍‬ 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies͞ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4 ؉ T cells.HIV-1 infection ͉ antiretroviral drugs ͉ viral load ͉ relapse ͉ CD4

To evaluate the effects of HIV infection on T cell turnover, we examined levels of DNA synthesis in lymph node and peripheral blood mononuclear cell subsets by using ex vivo labeling with BrdUrd. Compared with healthy controls (n ‫؍‬ 67), HIV-infected patients (n ‫؍‬ 57) had significant increases in the number and fraction of dividing CD4 ؉ and CD8 ؉ T cells. Higher percentages of dividing CD4 ؉ and CD8 ؉ T cells were noted in patients with the higher viral burdens. No direct correlation was noted between rates of T cell turnover and CD4 ؉ T cell counts. Marked reductions in CD4 ؉ and CD8 ؉ T cell proliferation were seen in 11͞11 patients 1-12 weeks after initiation of highly active antiretroviral therapy (HAART). These reductions persisted for the length of the study (16 -72 weeks). Decreases in naïve T cell proliferation correlated with increases in the levels of T cell receptor rearrangement excision circles. Division of CD4 ؉ and CD8 ؉ T cells increased dramatically in association with rapid increases in HIV-1 viral loads in 9͞9 patients 5 weeks after termination of HAART and declined to pre-HAART-termination levels 8 weeks after reinitiation of therapy. These data are consistent with the hypothesis that HIV-1 infection induces a viral burden-related, global activation of the immune system, leading to increases in lymphocyte proliferation.AIDS ͉ proliferation ͉ immune activation ͉ T cell receptor rearrangement excision circles H IV-1 infection is associated with a failure in T cell homeostasis, resulting in a gradual decline in CD4 ϩ T cell numbers. Studies examining lymphocyte turnover rates during infection with HIV or simian immunodeficiency virus have generated mixed results. Most of these discrepancies are likely the result of differences in the methods used to measure turnover rates, the use of longitudinal as opposed to cross-sectional cohorts, or the sensitivity and specificity of the assays used.An initial study of lymphocyte turnover rates using 3 Hthymidine to label CD4 ϩ and CD8 ϩ T cells found increased turnover rates in patients with HIV-1 infection (1). Studies of lymphocyte turnover derived through analysis of immediate changes in CD4 ϩ T cell counts in the blood after highly active antiretroviral therapy (HAART) also led to estimates of high rates of CD4 turnover (2-4), although others have suggested that lymphocyte redistribution may be the major cause for CD4 increases immediately after HAART (5-8). Measurements of lymphocyte proliferation using Ki-67, BrdUrd, and 2 H-glucose have yielded varying results (9-19); however, the general consensus is that T cell proliferation is increased in HIV͞simian immunodeficiency virus-infected subjects. Variations in these studies may be caused by the difference in sample numbers, cross-sectional versus longitudinal studies, patient cohort composition, and whether one is measuring the absolute or fractional level of cell division.To gain better insight into the immunopathogenic effects of HIV-1 infection, and to attempt to resolve some of the controversy...