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Abstract
Complex virus-host interactions are necessary for virus production and latency in the sensory neurons of infected cattle. Understanding the latency-reactivation cycle of BHV-1 has clinical and economic importance.
BHV-1 infected-cell protein 0 (bICP0) stimulates productive infection by activating viral gene expression. A bICP0 null protein virus was constructed and its growth properties investigated in cultured cells. Infection of bovine cells with the bICP0 null mutant resulted in at least 100-fold lower virus titres, indicating that bICP0 protein expression is important, but not required, for productive infection. When bovine cells infected with the bICP0 null mutant were subcultured, the cells continued to divide, but viral DNA was detected after more than 35 passages.
Further studies indicated that the bICP0 null mutant induced lower levels of apoptosis or necrosis relative to a bICP0 expressing virus. In addition, the bICP0 null mutant did not alter the cell cycle or stimulate a simple promoter containing an interferon stimulated response element. Collectively, these results indicated that bICP0 protein expression was important for efficient productive infection, and suggested that the bICP0 null mutant established a persistent-like infection in bovine cells.
Latency-related (LR) gene products inhibit apoptosis, bICP0 expression, and mammalian cell growth. The cell growth inhibitory function of the LR gene was mapped to a 463-bp XbaI-PstI fragment located at the 5' end of the LR transcript. Expression of a LR strand-specific transcript, not a protein, correlated with growth inhibition in bovine and mouse cells. Thus, the LR gene encodes several products that regulate the latency-reactivation cycle.
The proper cellular environment is required for productive infection. Overexpression of the histone acetyltransferase p300 stimulated productive infection potentially through its interaction with bICP0. Overexpression of the cellular transcription factor C/EBPα also stimulated productive infection. In summary, these studies indicated that bICP0 and cellular transcription factors have the potential to activate viral gene expression, and productive infection.
