I'm having an issue with some of my SEP clients not updating A/V definitions from the SEPM server.

Since differential updates are normally small, in an environment where all the traffic is on the same local LAN as the SEPM, it almost is never beneficial to use GUPs in this scenario.
While some bandwidth could be recovered by putting a GUP on each subnet, the management of a large-scale GUP environment in a local LAN will likely take more time and effort than any nominal bandwidth savings.
One of these computers may be a server (A pharmacy or a grocery store for example), or there may only be workstations, as in banks.
The network to the branch office does not have a large amount of bandwidth.
These updates occur roughly three times a day on average.
While in the field we have seen clients use GUPs in different ways, the purpose of the GUPs was to reduce bandwidth requirements.
If the client is not able to download the definition from the GUP due to the amount of time it takes or if the GUP is unavailable, it will then default to pulling definitions from the SEPM.
This is to insure that definitions are available to the client even if GUPs are unavailable. To understand the bandwidth savings of using a GUP it is important to understand the amount of traffic generated by definitions updates.
If the GUP does not have a definition it will reach out to its defined SEP Manager and download the correct update.