Discovery of HIV-1 Rev Nucleocytoplasmic Shuttling and Signald Mediated Active Export from the Nucleus

During the 1990s the group focussed on the mechanism of function of the HIV-1 Rev protein. This work was started in collaboration with Professor William A. Haseltine at Dana Farber Cancer Institute, Harvard Medical School in Boston, USA in 1990 and continued at the University of Bergen in 1991. Based upon our development of new anti-Rev hybridomas, new subcellular imaging technology and microinjection studies we first discovered that Rev is a nucleocytoplasmic shuttle protein (Kalland et al., 1994) and thereafter that a short leucine-rich domain of Rev is responsible for energy-dependent, signal-mediated protein export from the nucleus (Szilvay et al., 1995).

Studies of HIV-Rev subcellular trafficking thus led to the discovery of signal-mediated protein export from the nucleus. At the time it was a widely held alternative view that passage of proteins from the nucleus to the cytoplasm occurred due to a passive default mechanism unless proteins were retained in the nucleus due to molecular interactions. It is now known that signal-mediated protein export from the nucleus is essential in the life cycles of all viruses that replicate in the nucleus, and that this conserved eukaryotic transport mechanism is crucial in the regulation of the cell cycle and in the modulation of many signal-transduction pathways.