In OTL, contact between the Europeans and the American Indians introduced a vast and destructive wave of diseases which would have fucked up the locals if the Europeans had been the most pleasant people in the world.
The challenge is thus: make the American Indians maintain the majority of their population despite introduction to Old World powers (East or West), but have a PoD after the Black Plague first subsided in 1350. They need to avoid any similar depopulation events in the future as well.