Abnormal intracellular kinetics of cell-cycle-dependent proteins in lymphocytes from patients infected with human immunodeficiency virus: A novel biologic link between immune activation, accelerated T-cell turnover, and high levels of apoptosis
| Autor: | Barbara Cervasi, Mauro Magnani, Giuseppe Piedimonte, Gionata De Vico, Denise Guetard, Isa Picerno, M. Paiardini, Giuseppe Cannavò, Maria L. Bocchino, Guido Silvestri, Domenico Galati, Maria Montroni |
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| Přispěvatelé: | Cannavo, G, Paiardini, M, Galati, D, Cervasi, B, Montroni, M, DE VICO, Gionata, Guetard, D, Bocchino, Ml, Picerno, I, Magnani, M, Silvestri, G, Piedimonte, G. |
| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Anti-HIV Agents
Lymphocyte Immunology Cyclin B Apoptosis Cell Cycle Proteins HIV Infections Biochemistry Immune system Cell Cycle Protein medicine Nucleolus Organizer Region Humans cdc25 Phosphatases HIV Infection Lymphocytes Cyclin B1 Kinetic Cyclin-dependent kinase 1 biology Cell Cycle Anti-HIV Agent Apoptosi Cell Biology Hematology T lymphocyte Cell cycle Phosphoproteins Kinetics medicine.anatomical_structure Phosphoprotein Cancer research biology.protein CDC28 Protein Kinase S cerevisiae Human |
| Popis: | 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 cell-cycle control in the immunopathogenesis of acquired immunodeficiency syndrome (AIDS), we studied the expression of cell-cycle-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 HIV-infected patients, resulting in a 5-fold increase in apoptosis. Overall, our data indicate that a profound dysregulation of cell-cycle 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. |
| Databáze: | OpenAIRE |
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