Definitely, this didn't start happening until after the latest patch installed.

I start playing and everything seems to be working, but then a combat starts. I place the cursor on my intended target, hit V for V.A.T.S. .... and nothing happens. So I finish the battle just using the mouse. But when the battle is over and I go to loot the bodies, E does _not_ open the loot panel. Nor does Tab work to open up the PipBoy. The WASD kills still work, and the Esc still opens the menu, but E and V definitely are not functioning. So I figure I can Save the game, Exit the game to desktop, and start another session and maybe a reboot with get my hotkeys working again. Uh-uh. Now I'm wondering if the Save itself was corrupted by whatever was causing the hotkeys to NOT function.

I don't know what changes that causes the hotkeys to start functioning again, but just as mysterious as when the keys stop working, they start working again. In and out. I've run the anti-virus software (Avast) and spyware zapper (MalwareBytes), but the problem keeps on cropping up.

Anyone, any ideas on what is causing this?

Windows XO (SP3)
Intel Core 2 Quad CPU Q8200 @2.33GHz (4 CPUs)
4 Gb RAM
NVidia GeForce GTX 460
1024 Mb graphic RAM,
258.96 NVidia driver
DirectX 9.0c

ADDENDA: Don't ask me why this works because I certainly do not know, but....

If, when the hotkeys cease to function, you QuickSave (F5) and then Load (not sure if QuickLoad (F9) does the trick as well) the game that you just QuickSaved, the hotkeys will function once again.

Weird.