Here's an issue our own Michelle Dixon ran into while working on the 4.5 beta. Note that her issue specifically mentions Microsoft Office but this can occur with any exceptionally large virtualized app:
Issue: After performing a Desktop Refresh on an Application Virtualization 4.5 Client, an attempt to open a Microsoft Office document may generate the following error message:
Windows cannot find <File Name>. Make sure you typed the name correctly, and then try again.
The Application Virtualization 4.5 client fails to open the document and instead the SFTTRAY status indicates that the package is loaded at 100% and the virtualized Microsoft Office application opens without displaying the document that you were attempting to open. No other errors may be generated by the Application Virtualization client or show up in the Event Log.
Cause: This issue can occur if DDE (Dynamic Data Exchange) times out before Feature Block 1 (FB1) of the virtualized application is loaded and then launched. Once the virtualized application has been opened once, and FB1 has been loaded on the client, this should no longer be an issue.
Note: You may also experience this behavior if the workstation that the Application Virtualization client is running on suffers from low performance hardware, or if the client is running on a virtual machines on an overtaxed host.
Resolution: This should not be an issue with physical client workstations with adequate hardware. If the document you are attempting to open is located on a shared network resource you may experience this issue if there are any type of latency issues occurring on the network. If you are experiencing this issue and are unable to address the underlying performance related causes, the virtualized Microsoft Office applications can be pre-loaded into the client’s cache using the SFTMIME command with the /LOAD switch.
J.C. Hornbeck | Manageability Knowledge Engineer
Here's an issue our own Michelle Dixon ran into while working on the 4.5 beta.  Note that her