For the longest time it's been the SOLO Lead (SLO100) for me, mixed with the German Ubersonic (Uber!). But, lately, with new (to me) guitars and new pickups (like the Elysian Valkyrie), I've been delving into the ANGL Meteor (ENGL Fireball) and Das Benzin Lead (Deizel!). Also just set up a preset with a REV Gen Red last week too.
Where I find the most tone love is taking two guitar tracks, with two different amps, and mixing them together. With each track bringing something different to the final tone. How that worked previously was mixing the SOLO Lead and the German Ubersonic, so one playthru of each amp preset, both panned left. Then played again individually through both panned right for a total of 4 guitar tracks (the link below was done with these two amp presets, tracked individually 4 times total).
As for cabs, I flit back and forth from a few of the 412s (Uber T75, Uber V30, Cali V30) to a Mesa OS412 IR from Ola Englund, depending on how it all mixes together. The OS412 sounds utterly massive and much fuller than any of the Helix cabs - which works very, very well for most of what I play, but with a low end heavy amp, it can sometimes be too much.