I've done the I-81 during both the summer and winter... summer to South Carolina, and during the winter to Syracuse for some shopping trips.
My main concern is the snow that blows in off the great lakes.
What I was thinking of doing was driving all the way down and crossing at Detroit, then heading down the I-75 this way we are ahead of the great lakes ...to avoid all the weather. Our first camping stop will be around Memphis Tnn.
Obviously .. we are still in the planning stages ..
2008 Nissan Frontier 4x4
2011 Rockwood A122