Human immunodeficiency virus (HIV)-infection is characterized by loss of CD4؉ T cells associated with high levels of immune activation, T-cell proliferation, and lymphocyte apoptosis. To investigate the role of intrinsic perturbations of cellcycle control in the immunopathogenesis of acquired immunodeficiency syndrome (AIDS), we studied the expression of cellcycle-dependent proteins in lymphocytes from HIV-infected patients. Cyclin B1 expression, Nucleolar Organizer Regions (NORs) number, and NORs area of distribution were all consistently increased in HIV-infected patients, but returned to normal after effective antiretroviral therapy, suggesting that viral replication is directly implicated in the genesis of the observed changes. Analysis of cyclin B1 intracellular turnover showed that the increased cyclin B1 expression is (1) caused by defective degradation in the presence of normal rates of synthesis, and (2) is temporally associated with decreased levels of ubiquitination. After in vitro activation of lymphocytes from healthy individuals, cyclin B1 and cdc25 expression and ubiquitination, p34 cdc2 activity, NORs morphology, and C23/nucleolin localization showed a 72-to 96-hour cyclic pattern that led to a biologic state similar to baseline. On the contrary, complex but consistent changes of the same indices followed activation of T lymphocytes from HIVinfected patients, resulting in a 5-fold increase in apoptosis. Overall, our data indicate that a profound dysregulation of cellcycle control is present in lymphocytes from HIV-infected patients. This finding may provide a novel biologic link between immune activation, accelerated lymphocyte turnover, and increased apoptosis during HIV infection. IntroductionHuman immunodeficiency virus (HIV)-infection induces a progressive depletion of CD4 ϩ T lymphocytes and high susceptibility to opportunistic infections. 1 The mechanisms of HIV-induced CD4 ϩ T-cell loss include the virus-mediated killing of infected cells as well as the death of uninfected bystander cells. 1,2 Among the indirect mechanisms that have been implicated in the lymphocyte depletion of patients with acquired immunodeficiency syndrome (AIDS), increased level of apoptosis may be significant. In HIV-infected patients, increased susceptibility to apoptotic cell death has been shown in CD4 ϩ and CD8 ϩ T lymphocytes and appears to be correlated with the general state of immune activation. [3][4][5][6] Interestingly, both increased propensity to apoptosis and overall levels of immune activation are reversed by the institution of effective anti-HIV therapy. 7,8 It is therefore likely that an abnormal relationship between T-cell activation/proliferation and occurrence of apoptosis may play a significant role in the lymphocyte depletion in the HIV-infected patient. 9,10 Lymphocyte activation in response to extrinsic signals ultimately results in either progression through the cell cycle, or activation of proapoptotic pathway(s). 11,12 Although influenced by many factors, the fate of activated T cells is e...

Increased and unscheduled expression of cyclin B and p34 cdc kinase is consistently observed in CD4 and CD8 cells from HIV-infected patients, both in vivo and after in vitro mitogenic stimulation. These alterations correlate with the level of viremia and may provide a link between the perturbation of lymphocyte proliferative homeostasis and the exaggerated propensity towards apoptosis.