The Allegheny Front, where the continental divide runs between Altoona, PA and Frostburg, MD, wouldn't be a particular challenge for HSR, because they're good at hillclimbing, and the mass of the trainset is nothing like loaded coal trains or intermodal double-stack trains which currently frequent this area.
LGV Sud-Est has 3.5% grades, for example; the Pennsylvania Railroad (now Norfolk Southern) Gallitzin-Horseshoe Curve-Altoona stretch is 1.85%, B&O (CSX) Sand Patch Grade further south is 2%.
Rather, overcoming the general ruggedness of the terrain is the greatest expense. Slower railroads can meander along rivers, but a HSR needs large sweeping curves (with large radii), requiring expensive fills or cuts or viaducts. Some tunnels would be needed to cross some of the linear ridges, just like the Pennsylvania Turnpike (and the predecessor railroad that used the same right-of-way) did. In fact, it's likely that an alignment would closely parallel the turnpike, as the landscape gets significantly more rugged south of Maryland or north of I-80.
A gentler route following the Empire Corridor (roughly, NYC->Albany->Buffalo) may be cheaper to construct, but would be considered a "detour" by a casual observer -- and the expense of the NYC->Albany portion may not make it worthwhile.
Sadly, it's not very likely that such a Mid-Atlantic-to-Chicago passenger-only railway could be economical to construct and operate. US infrastructure costs routinely run much higher than the international average for comparable projects, and even the as-the-crow-flies distance (1100+ km, 700+ miles) between NYC-Chicago puts it too far out of HSR's ideal range, even in countries where people actually ride trains.