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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1756-1764
IMMUNOBIOLOGY
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
Giuseppe Cannavo',
Mirco Paiardini,
Domenico Galati,
Barbara Cervasi,
Maria Montroni,
Gionata De
Vico,
Denise Guetard,
Maria L. Bocchino,
Isa Picerno,
Mauro Magnani,
Guido Silvestri, and
Giuseppe Piedimonte
From the Dipartimento di Patologia Generale, Malattie
Infettive ed Ispezione degli Alimenti, Facolta' di Medicina
Veterinaria, Universita' degli Studi di Messina, Italy; Dipartimento
di Igiene, Medicina Preventiva e Sanita' Pubblica, Facolta' di
Medicina e Chirurgia, Universita' degli Studi di Messina, Italy;
Istituto di Chimica Biologica "G. Fornaini," Universita' di
Urbino, Italy; Servizio di Immunologia Clinica, Facolta' di Medicina e
Chirurgia, Universita' di Ancona, Italy; Unite de Oncologie Virale,
and Department SIDA et Retrovirus, Institut Pasteur, Paris, France;
Department of Pathology and Laboratory Medicine, Hospital of the
University of Pennsylvania, Philadelphia, PA.
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.
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