I play game that use GameGuard and Def + needs to be disabled my question is will Comodo A/V still sandbox files with Def + Permently Disabled ??? Becauase restarting everytime i wanna play a game will get old fast 
It says right in the Sandbox Settings dialog “If Defense+ is deactivated permanently, this option will have no effect,” so I think the answer is no.
Does it work if you add GameGuard (whatever program files it needs) to the Trusted files list? Look in your Unrecognized file list and move it into your Trusted list, or open up your Trusted list and add the files directly (see the Defense+ tab).