I've thought about this some.
It seems to me that the PRR is the way to go, at least to Pittsburgh. From there, there are multiple options to Cleveland-Toledo-Chicago, including possibly branches Detroit or Ft. Wayne. (It could also go right through Ft. Wayne directly.)
I like this route because it is direct and it serves some big metros. Most of the benefit of a NYC-Chi route would not be travel between New York and Chicago, but rather the points in between. This route directly serves Philly, Pittsburgh, Cleveland, Toledo, and northern Indiana cities (South Bend or Ft. Wayne). It could easily serve Youngstown or Akron. Connecting at Philly would be better for Washington or Baltimore passengers. A branch to Detroit would be pretty efficient. You could consider it the Boston-Milwaukee (Sam Adams-Schlitz) route too, since the NEC just continues through NYP and there is direct Chicago to Milwaukee service.
Between Harrisburg and Pittsburgh, there would be a number of new grades and tunnels. The goal would be to shorten the route by cutting off some of the more circuitous sections. (For example, this section between Altoona and Huntington:
http://maps.google.com/maps?f=q&hl=en&l ... 92139&om=1)
And this would be a big challenge, although it is something than can be done incrementally, one section at a time, with ever shorter travel times.
Remember that HSR has the potential to climb much steeper grades that freight trains; quick changes in grade a the real problem.