If you decide to come down the "Great Valley" -- roughly, head south to Chambersburg and follow U.S. 11 to Birmingham...

There's a lot of scenic climbing along Skyline Drive and Blue Ridge Parkway from Front Royal down to Roanoke, where the BRP veers more to the south. Nice road, usually low traffic except around Roanoke. I've wanted to try the New River Trail from near the Parkway downstream to Radford. The Adventure Cycling Trans America route has some good ideas to get you from there close to the Tennessee state line (Damascus, VA).

U.S. 411 south of Maryville, TN, has four lanes and decent shoulders to roughly Etowah. Traffic isn't too bad for the most part.

U.S. 11 and 411 in Alabama are surprisingly nice cycling routes. 11 may have slightly lower traffic, most of it local, because it so closely parallels I-59. I'd skip Rome, GA if I were trying to link up the two sections of 411, and cut across NW Georgia into Centreville.