The mammalian cell can be compared to a great metro- politan city, containing a central storehouse of informa- tion, power plants that generate energy, manufacturing districts, ports of entry and exit and an elaborate trans- portation system. Viruses, like daily commuters enter- ing a city from the suburbs, must find their way into the cell, move to specific intracellular locations to carry out essential tasks and then, after replication, find their way back out of the cell again. We are beginning to appre- ciate that the intracellular movement of viruses often exploits cellular transport systems that are designed to move host proteins or complexes. Indeed viruses, being large, visible by electron microscopy, and with potent effects on the host, can function as valuable reporters of the activities of these transport pathways 1 . Many viruses seem to have acquired the ability to use any of several transportation systems redundantly 2 , and so are not easily blocked by inhibitors of any one system. Like experienced commuters who are not fazed by flooded subways or clogged highways, viruses can be flexible in how they travel. Retrovirus replication has many steps in common with the replication of other viruses, as well as several steps that are unique to their life style (FIG. 1). Retroviruses bind to specific receptors on the cell surface (reviewed in REFS 3,4) and then, like all enveloped viruses, fuse the virion membrane with the host membrane, either at the cell surface or after internalization into endosomes, to deliver the virion core into the cytoplasm. This core particle, now named the reverse transcription complex (RTC), activates reverse transcriptase (RT) to copy the single-stranded positive-sense RNA genome into double- stranded linear DNA. This DNA is delivered into the nucleus in the form of a pre-integration complex (PIC) containing both viral and host proteins, and is then inserted into the host genome by the viral integrase pro- tein (IN) to form the integrated provirus. In the late phase of the life cycle, the viral DNA is transcribed by the host RNA polymerase II (RNAP) system, and the viral RNAs are processed and exported back out to the cytoplasm by highly regulated mechanisms 5 . Three viral structural protein precursors — group-specific-antigen protein (Gag), Gag-polymerase (Gag-Pol) and the envelope pro- tein (Env) — are translated in the cytoplasm, and trans- ported to the plasma membrane by vesicular, cytoskeletal or other routes. Nascent virions are assembled from these proteins on host membranes, and immature particles are released from the cells. Finally, maturation of the virions, which is triggered by the viral protease, results in a drastic reorganization of the core and the acquisition of virus infectivity. Because of retroviruses’ limited genome size and content, each step in this elaborate process requires the assistance of multiple host proteins (TABLE 1). This article reviews the rapidly expanding information about the host gene products and pathways, many of which are newly identified, that are involved in the replication and intracellular movements of retroviruses. Early steps: entry and uncoating After binding to receptors, many viruses trigger a response from the cell that is required for their sub- sequent uptake 6 . Entry of such viruses can be blocked by RNA interference (RNAi)-mediated knockdown of specific cytoskeletal proteins, with indications that both clathrin and non-clathrin dependent pathways could be involved 2 . There is little data to indicate that these pathways are involved in retrovirus infection, although observation of the movement of GFP-labelled virions supports this notion (see REF.7 for a recent review). After binding of HIV-1 virions to their receptor CD4, the virus particles trigger a remarkable sliding move- ment along the surface of cells in culture (surfing), until they arrive at selected sites where fusion and entry actually occur 8 . Frequently the virions initially bind at the tips of microvilli, and then move inward to the cell body before entry. The motors that drive this movement, and the link between the motors and the cytoplasmic side of the receptors that must be moved, have not been characterized. Fusion of HIV-1 virions may also involve the clustering of receptor molecules in Department of Biochemistry and Molecular Biophysics; and Department of Microbiology, Howard Hughes Medical Institute HHSC 1310c, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York, New York, 10032 USA. e-mail: goff@cancercenter. columbia.edu doi:10.1038/nrmicro1541 Published online 26 February 2007 Provirus Retrovirus particles contain an RNA genome, but after infection the RNA is reverse transcribed into DNA, which is inserted into the host-cell genome to form the integrated viral DNA, or provirus. The proviral DNA is a latent form of the virus genome that can be transcribed to produce infectious virus. Host factors exploited by retroviruses Stephen P. Goff Abstract | Retroviruses make a long and complex journey from outside the cell to the nucleus in the early stages of infection, and then an equally long journey back out again in the late stages of infection. Ongoing efforts are identifying an enormous array of cellular proteins that are used by the viruses in the course of their travels. These host factors are potential new targets for therapeutic intervention. NATURE REVIEWS | MICROBIOLOGY VOLUME 5 | APRIL 2007 | 253 REVIEWS © 2007 Nature Publishing Group