A Very Late Viral Protein Triggers the Lytic Release of SV40

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Abstract
How nonenveloped viruses such as simian virus 40 (SV40) trigger the lytic release of their progeny is poorly understood. Here, we demonstrate that SV40 expresses a novel later protein termed VP4 that triggers the timely lytic release of its progeny. Like VP3, VP4 synthesis initiates from a downstream AUG start codon within the VP2 transcript and localizes to the nucleus. However, VP4 expression occurs ∼24 h later at a time that coincides with cell lysis, and it is not incorporated into mature virions. Mutation of the VP4 initiation codon from the SV40 genome delayed lysis by 2 d and reduced infectious particle release. Furthermore, the co-expression of VP4 and VP3, but not their individual expression, recapitulated cell lysis in bacteria. Thus, SV40 regulates its life cycle by the later temporal expression of VP4, which results in cell lysis and enables the 50-nm virus to exit the cell. This study also demonstrates how viruses can generate multiple proteins with diverse functions and localizations from a single reading frame. The release of viral particles from an infected host cell is essential for a virus to spread within the host organism. Cytolytic viruses such as the common cold, poliovirus, and simian virus 40 (SV40) release their progeny by inducing lysis or death of the host cell. For efficient viral spreading, it is critical that optimal numbers of the virus are assembled before cell lysis and release occurs. Therefore, the timing of cell lysis is an integral and well-controlled step in the viral life cycle. For many years, lysis has been thought to be a nonspecific consequence of viral protein overexpression and the massive production of viral progeny. As SV40 was the first mammalian virus sequenced almost 30 years ago, it is an excellent model virus for investigating the poorly understood mechanism of viral release. In this study, we have identified a novel SV40 protein named VP4 that is required for the timely lytic death of the host cell, and hence regulates the spread of SV40. The late expression of VP4 offers a sufficient period for virion assembly to occur before it initiates the lytic release of the newly assembled viral progeny.