Induction of chromosome aberrations and mitotic arrest by cytomegalovirus in human cells

Abstract

Human cytomegalovirus (CMV) is potentially an effective but often overlooked genotoxic agent in humans. We report here evidence that indicates that infection by CMV can induce chromosome alterations and mitotic inhibition. The frequency of chromosome aberrations induced was dependent on the input multiplicity of infection (m.0.i.) for human lung fibroblasts (LU), but not for human peripheral blood lymphocytes (PBLs) when both cell types were infected at the GO phase of the cell cycle. The aberrations induced by CMV were mostly chromatid breaks and chromosome pulverizations that resembled prematurely condensed S-phase chromatin. Pulverized chromosomes were not observed in LU cells infected with virus stocks that had been rendered nonlytic by UV-irradiation at 24,000 ergs/mm2 or from infection of human lymphocytes. In LU cells infected with UV-irradiated CMV, the frequency of aberrations induced was inversely dependent on the extent of the exposure of the CMV stock to the UV-light. In permisive CMV infection of proliferating LU cells at 24 hr after subculture, a high percentage (> 40%) of the metaphase cells were arrested at their first metaphase and displayed severely condensed chromosomes when harvested 48 hr later. A significant increase (p < 0.05) in the chromosome aberration frequency was also observed. Our study shows that CMV infection is genotoxic to host cells. The types and extent of damage are dependent on the viral genome expression and on the cell cycle stage of the cells at the time of infection. The possible mechanisms for induction of chromosome damage by CMV are discussed.

E2F mediates dihydrofolate reductase promoter activation and multiprotein complex formation in human cytomegalovirus infection.

“…Furthermore, it has long been known that HCMV perturbs the cell cycle and can lead to chromosome damage (1,53,60,67). A careful comparison of E2F complex binding during HCMV infection and the normal cell cycle could provide clues about possible mechanisms for these effects and for the function of E2F complexes.…”

Human cytomegalovirus induces JC virus DNA replication in human fibroblasts.

“…It is conceivable that HCMV might not only enhance replication of archetype JCV but in addition might promote this adaptation process by an active contribution to the rearrangement of the JCV regulatory region. This is suggested by the fact that HCMV has been shown to induce host-cell repair replication and chromosomal aberrations in human fibroblasts (39,40). Likewise for HSV the induction of genetic instability, including point mutations and DNA amplification within the host cell genome, or recombination between duplicated target DNA sequences has been characterized.…”

Cell Activation Signals and the Pathogenesis of Human Cytomegalovirus

“…genotoxic damage) ap pears to be related to the CMV-induced cel lular physiologic changes. The type of geno toxic effects induced by CMV infection -G /S phase premature chromosome conden sation, C-mitosis and disrupted centromeres -suggest that CMV infection perturbs the normal progression through the cell cycle [21]. The specific damage induced by CMV seems to be dependent on the stage of the cell cycle at the time of infection.…”