I have a HD400, and I use it as a pre for my old Rocktron Velocity power amp plugged into a 1x12" Marshall cabinet (although I wish I had a 2x12" or a 4x12"): this doesnt change my pre sounds with extra tweaking or, even worse, gain, and gives me a warm natural sound.
I have connected my HD400 to combos, but they all change my sound: I like my clean, crunch and hi-gain tones from the POD and I think just connecting it to a good (guitar) power amp is the best solution.