| Summary: | In order to promote infection, viruses must target their genomes to specific compartments within the host cell. I have used the parvovirus minute virus of mice (MVM) as a model to study the trafficking of non-enveloped viruses. Parvoviruses are single-stranded DNA viruses which replicate in the nucleus of the cell. Most viruses that replicate in the nucleus transport their genomes through nuclear pore complexes, large protein assemblies that mediate nucleocytoplasmic transport. However, previous studies have shown that MVM can induce disruption of the nuclear membranes, called the nuclear envelope (NE). This led to the hypothesis that MVM enters the nucleus by an unusual mechanism: disruption of the NE and entry through the resulting breaks.
The objectives of this thesis were to: (1) characterize the effect of MVM on the NE, (2) define the molecular mechanism used by MVM to induce NE disruption, (3) determine the role of NE disruption in the MVM replication cycle, and (4) identify host proteins involved in MVM infection. I found that MVM causes small, transient disruptions of the NE early during infection. I tested the hypothesis that viral enzymatic activity is necessary for MVM-induced NE disruption and found that this was not the case. Next I tested the hypothesis that MVM hijacks a cellular program for NE breakdown, and found that MVM utilizes apoptotic proteases called caspases to facilitate these disruptions. Caspase inhibition prevents NE disruption in MVM-infected cells, reduces viral gene expression, and prevents entry of MVM capsids into the nucleus. I propose that NE disruption involving caspases facilitates parvovirus genome delivery into the nucleus. NE disruption also alters the compartmentalization of host proteins, which may be favorable for the virus.
I have shown that MVM uses a novel nuclear entry strategy, unlike those previously described for any virus or cellular protein. It will be of great interest to determine whether this strategy is shared by other viruses. Parvoviruses are not considered a serious threat as human pathogens. However, they may prove useful as vectors for gene therapy. An understanding of the basic biology of parvoviruses could help in the development of parvovirus-based therapeutics.
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