Coxsackievirus replication and the cell cycle: a potential regulatory mechanism for viral persistence/latency

Feuer, Ralph; Mena, Ignacio; Pagarigan, Robb R.; Hassett, Daniel E.; Whitton, J. Lindsay

doi:10.1007/s00430-003-0192-z

Cited by 35 publications

(26 citation statements)

References 41 publications

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“…We speculate that, between 24 to 48 h p.i., the activation status of infected BM cells changes in vivo, facilitating the completion of a productive CVB3 infection, and that this fails to occur in vitro, when the cells have been removed from their normal anatomical microenvironment. This proposal is consistent with prior observations from our group, showing that CVB3 protein synthesis and productive infection are profoundly affected by the cell cycle status and that CVB3 may lie quiescent within cells, beginning to replicate only when the cell status is changed (15,(56)(57)(58)(59); for example, neural stem cells in the SVZ are infected by CVB3 but still can migrate, and we have proposed that productive infection ensues only when the cells reach their final destination and complete their differentiation into mature neurons (13,15). Interestingly, hematopoietic progenitor cells in the BM are usually in a quiescent state and are roused from their dormancy by type I interferon (60), a cytokine that is produced early in response to CVB3 infections (Fig.…”

Section: Discussionsupporting

confidence: 93%

Coxsackievirus B3 Infects the Bone Marrow and Diminishes the Restorative Capacity of Erythroid and Lymphoid Progenitors

Althof

Whitton

2013

J Virol

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Coxsackievirus B3 (CVB3) is known to infect stem cells in the neonatal central nervous system. Here, we evaluated the effects of CVB3 infection on the major source and repository of stem cells, the bone marrow (BM). Viral genome was detectable in BM within 24 h of infection, and productive infection of BM cells was evident, peaking at 48 h postinfection (p.i.), when ϳ1 to 2% of BM cells produced infectious virus particles. Beginning at 2 to 3 days p.i., a dramatic and persistent loss of immature erythroid cells, B and T lymphocytes, and neutrophils was observed in BM and, by day 3 to 4 p.i., the femoral BM stroma was largely destroyed. Analysis of peripheral blood revealed a modest neutrophilia, a loss of reticulocytes, and a massive lymphopenia. The abundance of multipotent progenitor cells (Lin ؊ /c-kit ؉ /Flt3 ؉ ) in BM declined ϳ10-fold during CVB3 infection and, consistent with a deficiency of primitive hematopoietic progenitors, serum levels of the hematopoietic growth factor Flt3 ligand were dramatically elevated. Therefore, we analyzed the regenerative capacity of BM from CVB3-infected mice. Granulocyte/macrophage progenitors displayed a relatively normal proliferative ability, consistent with the fact that the peripheral blood level of neutrophils-which are very short-lived cells-remained high throughout infection. However, erythroid and lymphoid hematopoietic progenitors in BM from CVB3-infected mice showed a markedly reduced colony-forming capacity, consonant with the observed loss of both lymphocytes and immature erythroid cells/reticulocytes from the BM and peripheral blood. In summary, CVB3 infects the BM and exerts differential effects on the various hematopoietic progenitor populations.

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Section: Discussionsupporting

confidence: 93%

Coxsackievirus B3 Infects the Bone Marrow and Diminishes the Restorative Capacity of Erythroid and Lymphoid Progenitors

Althof

Whitton

2013

J Virol

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“…monolayers (data not shown). The pattern of labeling observed was not restricted to and it was no more intense at or near the injury site as has been reported for other viruses [11,12]. These observations agree with findings of other FMDV workers [13], indicating proliferating cells do not preferentially support viral replication.…”

Section: Viral Replication Does Not Preferentially Occur In Proliferasupporting

confidence: 81%

“…Furthermore, the eIF4E subunit of eIF4F is dephosphorylated at the G 2 /M stage, and this is correlated with diminished cap-dependent translation [9]. On the other hand, cells forced into G 0 , by either serum starvation or wounding of monolayers, did not show an increase in copy numbers of viral genome, as observed with other Picornaviruses [12] in which viral replication does not preferentially occur in proliferating cells.…”

Section: Discussionmentioning

confidence: 53%

Dynamics of foot-and-mouth disease virus replication in cells at different phases of the cell-division cycle

Doel¹,

Zhang²,

Mazelet³

et al. 2014

Front. Agr. Sci. Eng.

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Foot-and-mouth-disease virus (FMDV) replicates in epithelial cells. The restriction of FMDV RNA to the basal cell layer of epithelia suggests a possible link between FMDV replication in vivo and the cell status. This paper describes in vitro studies in which FMDV infection was investigated in cells that were held at various cell division phases using cell cycle inhibitors. The results suggest that when cells were arrested at the G 1 or G 1 /S phase, high levels of viral RNA were detected by quantitative real-time reverse transcription PCR and viral protein synthesis was observed by specific labeling techniques. In contrast, when cells were arrested at the G 2 /M phase, reduced or no viral RNA synthesis was detected.

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“…The association of CV with both acute and chronic inflammatory diseases in humans and the evidence for persistence of picornavirus RNA in vivo long after initial infection led to the proposal that cell cycle status of the host cell may influence CV persistence, replication, and disease manifestations (25). This proposal was supported in a mouse model of infection (23,24). Finally, RNA replication (58) and translation of HCV (36,66) were shown to be modulated by cellular growth state through the use of reporter constructs and replicons.…”

Section: Discussionmentioning

confidence: 99%

S-Phase-Dependent Enhancement of Dengue Virus 2 Replication in Mosquito Cells, but Not in Human Cells

Helt

Harris

2005

J Virol

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Dengue virus (DEN) is the most prevalent cause of arthropod-borne viral illness in humans. We determined the influence of cellular growth state on DEN type 2 (DEN2) replication in mosquito and human cells, based on the hypothesis that manipulation of cellular growth state will facilitate identification of viral and cellular determinants of productive infection. Comparison of density-arrested and cycling C6/36 Aedes albopictus cells infected with a low-passage DEN2 isolate revealed that cycling cells generated higher virus titers per cell. When C6/36 cells were stalled in S-phase via a thymidine (THY) block, titers of low-passage DEN2 isolates and a high-passage strain, 16681, were increased approximately 30-fold and 10-fold, respectively. Moreover, virus release was earlier in THY-treated cells than in asynchronously cycling cells. Adsorption, entry, genome uncoating, and translation were not responsible for increased titers of virus from S-phase C6/36 cells. In contrast to the 30-fold increase in virus titers, intracellular levels of viral RNA were increased approximately 2-fold, suggesting that the S-phase-responsive step is late in the DEN2 replication cycle. Analysis of viral RNA and protein released from the cells indicated that enhanced DEN2 assembly is largely responsible for increased virus titers produced during S-phase. In contrast to C6/36 cells, DEN2 titers from S-phase human hepatoma cells or primary human fibroblasts were not increased. These results demonstrate a differential response of DEN2 to the mosquito and human cell cycle and provide a framework for detailed studies into the mechanisms mediating virus assembly.Dengue virus (DEN) is a member of the Flaviviridae, a family of positive-strand RNA viruses that includes hepatitis C virus (HCV), West Nile virus, and yellow fever virus, among others. DEN is a widespread public health problem, with an estimated 50 million cases per year of dengue fever and 250,000 to 500,000 cases of more severe, life-threatening forms of the disease (29). The expanding distribution of the mosquitoes that transmit DEN, Aedes aegypti and Aedes albopictus, places nearly half of the world's population at risk for infection with one of the four serotypes (DEN1 to -4), yet there are no antiviral treatments or vaccines available against DEN. Moreover, the viral and host determinants governing DEN replication are not well understood in either the human or mosquito hosts.Upon infection of the host cell and uncoating of the viral genome, translation of the DEN polyprotein proceeds (48). The polyprotein is cleaved co-and posttranslationally by viral and host proteases into three structural and seven nonstructural (NS) proteins. Viral RNA replication, directed by newly generated NS proteins, then ensues. Immature virions are assembled in the endoplasmic reticulum, or in endoplasmic reticulum-derived vesicles, and virion maturation occurs as the virus is secreted (48).Mosquitoes become infected with DEN by feeding on an infected human, and the mosquito remains infected during i...

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Coxsackievirus replication and the cell cycle: a potential regulatory mechanism for viral persistence/latency

Cited by 35 publications

References 41 publications

Coxsackievirus B3 Infects the Bone Marrow and Diminishes the Restorative Capacity of Erythroid and Lymphoid Progenitors

Coxsackievirus B3 Infects the Bone Marrow and Diminishes the Restorative Capacity of Erythroid and Lymphoid Progenitors

Dynamics of foot-and-mouth disease virus replication in cells at different phases of the cell-division cycle

S-Phase-Dependent Enhancement of Dengue Virus 2 Replication in Mosquito Cells, but Not in Human Cells

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