As far as interstates go, I-88 from the Albany area down to Binghampton, then I-81 all the way down to Knoxville where you can pick up I-40. Keeps you well west of NYC, north Jersey, the Philly area and pretty much all of Megalopolis. I haven't done it in 30 years, but the I-81 trip down the western spine of Virginia is a nice ride.
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