I take I95 up to I26 towards Columbia SC and pick up I77 in Columbia SC which will take you to I81. I've looked at the Atlanta/Chattanooga/Knoxville route, but it's almost 200 miles out of the way and at least 2-3 hours longer to get to I81. And you can stop in Mayberry (Mt Airy SC) for a nice little side trip!
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