$0.02
Your question is an interesting one. I don't think that guerilla tactics in western Pennsylvania could even be brought to bear because Lee, nor the Confederacy, have the resources required to sustain an aggressive offensive action. Without intending any disrespect, this is an Army and 'war machine' that cannot even provide shoes for its own soldiers, let alone materialize the resources to successfully execute this war. IMO, this is just a logistic and resource-based reality that, in the end, cannot be avoided. Regardless of whatever successes the Confederacy might have had initially, sustained effort is ultimately not possible for them (they never had the resources to execute this war, even from the beginning).
With regard to Vicksburg, I believe I understand what you're suggesting (i.e., "Admittedly it was already too late for Vicksburg, however Lee didn't nor could he have know this at the time,..."); however, the significance of Vicksburg trumps every other and any other strategic contingency the South might have pursued. [As an aside, Lee might not have known, but Davis did.]
In short, Vicksburg's long shadow will ultimately eclipse the South entirely and the South cannot survive with all its waterways cut off. The loss of Vicksburg in essence means the end of the war; everything after that is academic. To that end, it doesn't matter what Lee does once Vicksburg is gone. That's obviously my opinion and I recognize that it's an ambitious assertion. Nevertheless, I think that Vicksburg is still not recognized for the strategic boon it really was (no doubt it takes something of a backseat to the Eastern theatre, which is probably understandable to some extent). To this end, I think that discounting Vicksburg or approaching alternative strategies while pretending Vicksburg could be set aside for a hypothetical 'what if' are essentially defunct. I'm not suggesting at all that you're discounting Vicksburg (nor am I suggesting that your question is not worth pursuing); it's just that Vicksburg is so instrumental (I believe) that its loss cannot be mitigated in any way. In the final analysis, the loss of Vicksburg amounts to the capture of the queen; checkmate is sure to follow (no matter what happens in the east).