Police
Realistic police (killing NPC's won't give you a wanted level if no one sees you). K-9 dogs. After 4-stars you will have to lose the helicopter following you to have wanted level go down. Wanted level is not as easy to lose like in IV.
Weapon System
Dual wielding pistols. Wider arrange of melee weapons. More fluid animations. More blood and gore. Weapon customization: silencers on pistols or rifles (like in the trailer)
Enivironment
Larger city (2x size of IV). Huge countryside with full size mountain range and forest. Desert terrain. Small cities and many side missions to particpate in.
More interiors, vertically too. High rise building. Ability to buy apartments, condos, houses.
A diverse weather system: at one point it could be sunny and then you have a thunderstorm. Heavy fog, beautiful sunsets and sunrise, or drought in some parts of the country.
Transporation
Planes, car customization, body shops, bicycles, jet skis.
Clothing
More stores! Suits for that party overlooking Los Santos or sweats when you have a messy job to take care of. Lots of different choices.
Storyline
A long storyline (like IV). Character cameo's from IV or other GTA's.