Assuming that we are only talking about one guitarist per HD500, then the really easy answer is to get a JTV Variax - it has a  tuning knob that simulates a set of alternative tunings and you can overwrite the ones you don't like with others that you do want. If you use the VDI connection you can link virtual guitars and tunings to the Patches on the POD - I have patches in a single bank for 12 string and 6 string acoustics, les paul into Marshall Plexi and a Bass.  The latter is the JTV with tuning down 12 semitones controlled by the HD into the Bass Amp sim. 

Outside of the JTV solution can you connect 4 guitars to a Pod HD500 without having to change cables all the time?

Well there is the Guitar Input and the Aux Input, and the Mic Input which I haven't tried with a guitar but should work with a tweak of the trim control.

That gives 3 and you can control which of those are active using the Input configuration settings on any patch.

But if you are not using the 4CM you have two additional inputs that could also be added to the signal path - the L+R FX Loop Returns.  If you place the FX Loop Effect at the start of the Patch and tweak the gain settings it should be possible to have the FX loop inputs feed in as well.

So it is theoretically possible to have 5 guitars all connected to a POS HD500 and all active at the same time and sharing the same Amp and Effects.

The main disadvantage of connecting multiple inputs at the same time and having those inputs active is the accumulated noise; so you will want to mute the unused inputs as you change guitars which I think would start to be a real pain in the back, so personally I would go with the tried and tested method of sharing any Amp between multiple guitars by only using the Guitar input and plugging and unplugging at the Guitar end of the cable.

Actually that last statement is what I did do when I had two guitars with different tunings, but now I have the much simpler to control and incredibly flexible set-up - I have a JTV Variax and VDI cable so I can change guitars and tunings every bar if I want with the press of a pedal.

Really, all i do is put the HD500 in tuner/mute mode and then switch guitars. Can't get any simpler than that.