n-Butyrate, a cell cycle blocker, inhibits the replication of polyomaviruses and papillomaviruses but not that of adenoviruses and herpesviruses

Abstract

Small DNA viruses are dependent on the interaction of early proteins (such as large T antigen) with host p53 and Rb to bring about the G,-to-S cell cycle transition. The large DNA viruses are less dependent on host regulatory genes since additional early viral proteins (such as viral DNA polymerase, DNA metabolic enzymes, and other replication proteins) are involved in DNA synthesis. A highly conserved domain of large T antigen (similar to the p53-binding region) exclusively identifies papovavirus, parvovirus, and papillomaviruses from all other larger DNA viruses and implies a conserved interaction with host regulatory genes. In this report, we show that 3 to 6 mM butyrate, a general cell cycle blocker implicated in inhibition of the G1-to-S transition, inhibits DNA replication of polyomavirus and human papillomavirus type 11 but not the replication of larger DNA viruses such as adenovirus types 2 and 5, herpes simplex virus type 1, Epstein-Barr virus, and cytomegalovirus, which all bypass the butyrate-mediated cell cycle bloclk This butyrate effect on polyomavirus replication is not cell type specific, nor does it depend on the p53 or Rb gene, as inhibition was seen in fibroblasts with intact or homozygous deleted p53 or Rb, 3T6 cells, keratinocytes, C2C12 myoblasts, and 3T3-L1 adipocytes. In addition, butyrate did not inhibit expression of polyomavirus T antigen. The antiviral elfect of butyrate involves a form of imprinted state, since pretreatment of cells with 3 mM butyrate inhibits human papillomavirus type 11 DNA replication for at least 96 h after its removal. Butyrate, therefore, serves as a molecular tool in dissecting the life cycle of smaller DNA viruses from that of the larger DNA viruses in relation to the cell cycle.

The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors.

“…In agreement with these observations of EBV replication in growth-arrested, differentiated cells in vivo, it has been shown in vitro that replication of EBV, as well as other herpes viruses, can occur in cells treated with agents shown previously to arrest cell cycle progression (Shadan et al, 1994). In contrast, replication of small DNA viruses such as SV40 and papillomavirus is inhibited by these reagents (Shadan et al, 1994). Since large DNA viruses, such as EBV, encode proteins involved in DNA synthesis (DNA polymerase, DNA metabolic enzymes and other replication factors), they are less dependent on the host cell DNA replication machinery than small DNA viruses, which have a strict requirement for inactivation of growth inhibitory signals provided by the tumor suppressor proteins pRb and p53 in order to promote S-phase progression (Vousden, 1995).…”

“…Full EBV replication appears to be highly dependent on the differentiated state of the epithelium since it is observed in the upper spinous layer which contains cells that have stopped dividing, but not in the basal, mitotically active layer (Wolf et al, 1984;Becker et al, 1991;Young et al, 1991). In agreement with these observations of EBV replication in growth-arrested, differentiated cells in vivo, it has been shown in vitro that replication of EBV, as well as other herpes viruses, can occur in cells treated with agents shown previously to arrest cell cycle progression (Shadan et al, 1994). In contrast, replication of small DNA viruses such as SV40 and papillomavirus is inhibited by these reagents (Shadan et al, 1994).…”

Requirement for Cellular Cyclin-Dependent Kinases in Herpes Simplex Virus Replication and Transcription

“…Equally as informative as the fact that Rosco and Olo inhibit HSV replication is the fact that other cell cycle and protein kinase inhibitors do not. In addition to the results presented in this report, n-butyrate, which inhibits cell cycle progression in late G 1 by inhibiting histone deacetylase, does not inhibit HSV replication (53). In another study, nine unique tyrosine kinase inhibitors inhibited HSV replication by only 10-fold after 24 h, most likely through direct inhibition of a viral function(s) (62).…”

Deciphering Novel Host–Herpesvirus Interactions by Virion Proteomics

“…Interestingly, HSV-1 does not require cells to be in the S-phase and even arrests the cell cycle at the G1/S transition step (Shadan et al, 1994;Song et al, 2000), which partly explains why it can grow in non-dividing neurons. While the precise mechanism of this arrest is unclear, it is known that the viral ICP0 protein and the VP16 cellular partner HCF modulate the cell cycle (Hobbs and DeLuca, 1999;Lomonte and Everett, 1999;Piluso et al, 2002).…”