Human herpesvirus 7 infection induces profound cell cycle perturbations coupled to disregulation of cdc2 and cyclin B and polyploidization of CD4(+) T cells.
Human herpesvirus 7 (HHV-7) infection of both primary CD4(+) T lymphocytes and SupT1 lymphoblastoid T-cell line induced a progressive accumulation of cells exibiting a gap 2/mitosis (G2/M) and polyploid content coupled to an increased cell size. The expression of both cyclin-dependent kinase cdc2 and cyclin B was increased in HHV-7-infected cells with respect to the uninfected ones. Moreover, the simultaneous flow cytometric analysis of cyclin B and DNA content showed that cyclin B expression was not only increased but also unscheduled with respect to its usual cell cycle pattern. However, the levels of kinase activity associated to cdc2 were decreased in HHV-7-infected cells with respect to uninfected cultures. To elucidate the origin of the enlarged HHV-7-infected cells, extensive electron and confocal microscopy analyses were performed. Membrane fusion events associated to cytoplasmic bridges, which characterize the formation of syncytia, were never observed. On the other hand, analysis of serial sections of the same cells strongly suggested that enlarged HHV-7-infected cells contained a single polylobated nucleus. This was confirmed by flow cytometry analysis performed on nuclei isolated from HHV-7-infected cells, which showed multiple peaks with a DNA content >4n. Taken together, these data indicate that giant cells, which represent the hallmark of in vitro HHV-7 infection, arise from single CD4(+) T cells undergoing a process of polyploidization.
Institute of Human Virology, University of Maryland at Baltimore, Baltimore, MD, USA.
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P
Secchiero
L
L
Bertolaso
L
L
Casareto
D
D
Gibellini
M
M
Vitale
K
K
Bemis
A
A
Aleotti
S
S
Capitani
G
G
Franchini
R C
RC
Gallo
G
G
Zauli
D015496:CD4-Positive T-Lymphocytes / Q000648:ultrastructure* / Q000821:virology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism*; D004247:DNA / Q000032:analysis; D005434:Flow Cytometry; D016195:G2 Phase; D006566:Herpesviridae Infections / Q000378:metabolism / Q000473:pathology*; D016199:Herpesvirus 7, Human; D006706:Homeostasis; D006801:Humans; D018613:Microscopy, Confocal; D008938:Mitosis; D019000:Phosphotyrosine / Q000378:metabolism; D011123:Polyploidy; D016196:S Phase
D019926:Cyclin B; D019000:Phosphotyrosine; D004247:DNA; D016203:CDC2 Protein Kinase