HIV-1 nuclear import: matrix protein is back on center stage, this time together with Vpr.

The ability of HIV-1 to transport its pre-integration complex (PIC) into the nucleus of an infected cell during interphase is a unique feature that sets this virus, and the whole group of Len-tiviruses to which it belongs, apart from other retroviruses that have to rely on the dissolution of the nuclear envelope during mitosis for delivery of their genome into the nucleus (1,2). Following initial reports demonstrating the central role of this process in the ability of HIV-1 to replicate in nondividing cells, such as macro-phages (3-5), the mechanisms of HIV-1 nuclear import have become the subject of intensive research. Early results (6) indicated that the process of nuclear import of HIV-1 genome is energy dependent, thus implying an active transport mechanism and suggesting that the virus is exploiting the cellular nuclear import machinery. This machinery transports into the nucleus those cellular proteins that carry characteristic nuclear localization signals (NLSs). The most common type of NLS is a short stretch of basic amino acids that introduce an overall net positive charge crucial for nuclear targeting properties of these sequences (reviewed in ref. 7). Import of basic-type NLS-containing proteins across the nuclear pore complex is mediated by karyo-pherin a/f3 heterodimers (also termed NLS re-ceptor/importin) which bind NLS-containing proteins in the cytosol and target them to the nucleus (8-1i). Karyopherin a binds the NLS, whereas karyopherin (3enhances the affinity of a Address correspondence and reprint requests to: Dr. for the NLS and mediates docking of the import complex to nucleoporins (a collective term for nuclear pore complex proteins) that contain xxFG peptide repeats (reviewed in ref. 12). A small GTP-binding protein, Ran/TC4 (13,14), is probably the major regulator of the directionality of nuclear transport (15). The direct binding of RanGTP to karyopherin ,B terminates the trans-location by disassembling the import complex (16-18). In addition to karyopherins and Ran, several other soluble proteins are involved in nuclear import, although their mechanism of action is less defined. The nuclear import factor p10 (also termed NTF2) (19,20) appears to coordinate the activity of Ran by binding Ran-GDP into a complex with nucleoporin-docked karyo-pherins (21). Heat-shock protein 70 (Hsp7O, Hsc7O), as well as some as yet uncharacterized cytoplasmic factors, may act to facilitate the interaction between the NLS and karyopherin a (22,23). The ectopic expression of human Hsp7O in mouse cells complemented the defective import of a mutant SV40 large T antigen (24), and the depletion …