I have been experiencing similar issues. I am running on Windows XP, the loop-back test works successfully, the ATmega2560 is enumerated within the list of available devices. I have an AVRISPmkii and an AVR One! in all cases I have been able to program the ATmega2560 with the ISP successfully. However, I am unable to program the 16u2 in order to restore it to an initial state. I am unable to program via USB in any of the Arduino Development environments going back to version 0022 so I don't think it is:
1> AVRISPmkii
2> AVR One!
3> Arduino Development environment
4> The ATmega2560
I am not sure if this helps but thought I would share my experiences in hopes that we can figure out why Arduino in conjunction with Atmel are turning out defective 2560 boards.