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• W2054165784 abstract "Microtubule-mediated transport of macromolecules and organelles (also known as “cargo”) is essential for cells to function. Deficiencies in cytoplasmic transport are frequently associated with severe diseases and syndromes. Cytoplasmic transport also provides viruses with the means to reach their site of replication and is the route for newly assembled progeny to leave the infected cell. This parasitic relationship of viruses with the host cytoskeleton provides an excellent basis for cell biologists to unlock the secrets of cytoplasmic transport and unravel mechanisms of disease. Recent advances in live cell imaging and computational tracking of fluorescently labeled viruses are now revealing how complex the movements of single viruses are in infected cells. This review focuses on microtubule-based motility of viruses and highlights the mechanisms regulating cytoplasmic transport. Microtubule-mediated transport of macromolecules and organelles (also known as “cargo”) is essential for cells to function. Deficiencies in cytoplasmic transport are frequently associated with severe diseases and syndromes. Cytoplasmic transport also provides viruses with the means to reach their site of replication and is the route for newly assembled progeny to leave the infected cell. This parasitic relationship of viruses with the host cytoskeleton provides an excellent basis for cell biologists to unlock the secrets of cytoplasmic transport and unravel mechanisms of disease. Recent advances in live cell imaging and computational tracking of fluorescently labeled viruses are now revealing how complex the movements of single viruses are in infected cells. This review focuses on microtubule-based motility of viruses and highlights the mechanisms regulating cytoplasmic transport. As every commuter knows, getting from one destination to another across any large busy city is not always so straightforward. The same is true for the movement of “cargoes” throughout the cytoplasm of eukaryotic cells, as the physical properties of the cytosol are far from ideal for macromolecular transport. Objects smaller than about 500 kDa diffuse freely in the cytoplasm, while objects larger than about 20 nm are macroscopically immobile due to the high viscosity of the cytosol and the presence of a dense meshwork of cytoskeletal filaments (Luby-Phelps, 2000Luby-Phelps K. Cytoarchitecture and physical properties of cytoplasm: volume, viscosity, diffusion, intracellular surface area.Int. Rev. Cytol. 2000; 192: 189-221Crossref PubMed Google Scholar). Regardless of the problem of moving in this difficult cellular environment, the function of every living eukaryotic cell is critically dependent on transport of macromolecules and organelles throughout the cytoplasm. Furthermore, the cytoplasmic transport of cargoes must be flexible, being able to respond in both a temporal and spatial fashion to the cell's ever-changing needs. Cargo transport throughout the cell is therefore a highly regulated process, which involves three different classes of molecular motors. Kinesin and dynein motors use microtubules as tracks to move cargo throughout the cytoplasm, while myosin motors interact with actin filaments to move their cargoes (Kamal and Goldstein, 2002Kamal A. Goldstein L.S. Principles of cargo attachment to cytoplasmic motor proteins.Curr. Opin. Cell Biol. 2002; 14: 63-68Crossref PubMed Scopus (91) Google Scholar, Karcher et al., 2002Karcher R.L. Deacon S.W. Gelfand V.I. Motor-cargo interactions: the key to transport specificity.Trends Cell Biol. 2002; 12: 21-27Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, King, 2003King S.M. Dynein motors: structure, mechanochemistry and regulation.in: Schliwa M. Molecular Motors. Wiley-VCH Verlag GmbH, Weinheim, Germany2003: 45-78Google Scholar, Schliwa and Woehlke, 2003Schliwa M. Woehlke G. Molecular motors.Nature. 2003; 422: 759-765Crossref PubMed Scopus (428) Google Scholar, Vale, 2003Vale R.D. The molecular motor toolbox for intracellular transport.Cell. 2003; 112: 467-480Abstract Full Text Full Text PDF PubMed Scopus (808) Google Scholar, Vallee et al., 2004Vallee R.B. Williams J.C. Varma D. Barnhart L.E. Dynein: an ancient motor protein involved in multiple modes of transport.J. Neurobiol. 2004; 58: 189-200Crossref PubMed Scopus (250) Google Scholar). Members of these three classes of motors constitute extended families, each with their own characteristic properties, domains, and associated subunits (see kinesin and myosin homepages, http://www.proweb.org/kinesin/ and http://www.mrc-lmb.cam.ac.uk/myosin/myosin.html). Genome-sequencing projects have provided most if not all the motor sequences in higher eukaryotes, while single-molecule experiments have started to uncover aspects of the molecular mechanisms of a number of these motors. The importance of motor-based transport is manifested in many different disease phenotypes, for example, the involvement of myosin II in muscle myopathies (Bonnemann and Laing, 2004Bonnemann C.G. Laing N.G. Myopathies resulting from mutations in sarcomeric proteins.Curr. Opin. Neurol. 2004; 17: 529-537Crossref PubMed Scopus (21) Google Scholar), or myosins VI, VIIa, IX, and XV in deafness (Muller and Littlewood-Evans, 2001Muller U. Littlewood-Evans A. Mechanisms that regulate mechanosensory hair cell differentiation.Trends Cell Biol. 2001; 11: 334-342Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Defects of microtubule-based transport are often most dramatically manifested in neuronal disorders, including amyotrophic lateral sclerosis or Alzheimer's disease (Hirokawa and Takemura, 2004Hirokawa N. Takemura R. Molecular motors in neuronal development, intracellular transport and diseases.Curr. Opin. Neurobiol. 2004; 14: 564-573Crossref PubMed Scopus (97) Google Scholar, Mandelkow and Mandelkow, 2002Mandelkow E. Mandelkow E.M. Kinesin motors and disease.Trends Cell Biol. 2002; 12: 585-591Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Given the clinical importance of microtubule-based transport, it is surprising that we still lack basic information about the nature and regulation of cargo binding and how motors work together to transport cargoes and maintain cellular architecture and function. Over the past few years, one of man's potentially biggest and smallest enemies, the virus, has begun to provide us with important insights into the complex problem of cytoplasmic transport. This is no surprise considering the nature of viruses. Viruses may date back to the very origins of life and are ubiquitous in today's organisms (Villarreal, 2004Villarreal L.P. Are viruses alive?.Sci. Am. 2004; 291: 100-105Crossref PubMed Google Scholar). They also represent a significant and ever-changing threat, as their short generation times and error-prone replication mechanisms promote for rapid evolution that can result in increased virulence or the ability to cross species boundaries with ensuing disastrous consequences (Beigel et al., 2005Beigel J.H. Farrar J. Han A.M. Hayden F.G. Hyer R. de Jong M.D. Lochindarat S. Nguyen T.K. Nguyen T.H. Tran T.H. et al.Avian influenza A (H5N1) infection in humans.N. Engl. J. Med. 2005; 353: 1374-1385Crossref PubMed Scopus (760) Google Scholar, Weiss, 2003Weiss R.A. Cross-species infections.Curr. Top. Microbiol. Immunol. 2003; 278: 47-71PubMed Google Scholar). Viruses, which range from about 20 to several hundred nanometers, are obligate parasites, as their genomes do not encode all the proteins required for replication. Nevertheless, even with their relatively small repertoire of proteins, they must still be capable of manipulating the necessary cellular functions of their host to achieve production of new progeny. This includes, for example, the capacity to inhibit apoptosis of the cell during replication, while at the same time minimizing detection by the immune surveillance systems of the host. Studying pathogens and their hosts, which have often coevolved for millions of years, has revealed fundamental insights into basic cell functions, including those needed for pathogen entry, replication, transport, and cell-to-cell spread (see also other reviews in this issue of Cell). In addition, these studies also provide novel observations and concepts for developing effective therapies that target the host rather than the virus. During their life cycle, viruses spread from cell to cell and must get from the plasma membrane to their site of replication and back again after replication. This can be a problem, since the size of viruses and the high density of the cytoplasm precludes efficient directional movements by free diffusion. It has been estimated that vaccinia virus, a relative of the causative agent of smallpox, would take ∼5 hr to diffuse a mere 10 μm in the cytoplasm of an infected cell (Sodeik, 2000Sodeik B. Mechanisms of viral transport in the cytoplasm.Trends Microbiol. 2000; 8: 465-472Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Furthermore, random diffusional movements are unlikely to drive virus particles to their desired destinations, thus reducing the speed of infection and overall viral fitness. Therefore, viruses have evolved efficient mechanisms to hijack the cellular transport systems of their unwilling hosts. In this review, we focus on how viruses use the microtubule cytoskeleton to enhance their spread of infection and highlight what they have taught us about cytoplasmic transport and what the future might hold. The first problem any virus faces after breaking into the cell is how to get to the replication site, which may be the nucleus, some distance away from the point of entry. In many cell types, the nucleus is positioned near the microtubule-organizing center (MTOC), where microtubules are preferentially nucleated and remain anchored by their minus ends (Bornens, 2002Bornens M. Centrosome composition and microtubule anchoring mechanisms.Curr. Opin. Cell Biol. 2002; 14: 25-34Crossref PubMed Scopus (320) Google Scholar). Microtubule-based transport of viruses toward the MTOC is very common, although there are rare reports claiming microtubule independent viral transport (Dohner et al., 2005Dohner K. Nagel C.H. Sodeik B. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins.Trends Microbiol. 2005; 13: 320-327Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, Sodeik, 2000Sodeik B. Mechanisms of viral transport in the cytoplasm.Trends Microbiol. 2000; 8: 465-472Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Some viruses, such as ebola virus (Yonezawa et al., 2005Yonezawa A. Cavrois M. Greene W.C. Studies of ebola virus glycoprotein-mediated entry and fusion by using pseudotyped human immunodeficiency virus type 1 virions: involvement of cytoskeletal proteins and enhancement by tumor necrosis factor alpha.J. Virol. 2005; 79: 918-926Crossref PubMed Scopus (74) Google Scholar) ride on microtubules within membranous compartments, and others, such as polyoma virus (Sanjuan et al., 2003Sanjuan N. Porras A. Otero J. Microtubule-dependent intracellular transport of murine polyomavirus.Virology. 2003; 313: 105-116Crossref PubMed Scopus (11) Google Scholar), can be membrane free. The nature of these membranes is highly diverse and known only in a few instances, such as influenza virus (Lakadamyali et al., 2003Lakadamyali M. Rust M.J. Babcock H.P. Zhuang X. Visualizing infection of individual influenza viruses.Proc. Natl. Acad. Sci. USA. 2003; 100: 9280-9285Crossref PubMed Scopus (274) Google Scholar) or simian virus 40 (see also review by Marsh and Helenius, 2006Marsh M. Helenius A. Virus entry: Open sesame.Cell. 2006; (this issue)PubMed Google Scholar [this issue of Cell]; Smith and Helenius, 2004Smith A.E. Helenius A. How viruses enter animal cells.Science. 2004; 304: 237-242Crossref PubMed Scopus (402) Google Scholar). Likewise, in many cases we still do not know from which membrane compartment the viruses escape to the cytosol for further trafficking to their site of replication. There is, however, unequivocal evidence for microtubule-dependent transport of naked virus particles (Dohner et al., 2005Dohner K. Nagel C.H. Sodeik B. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins.Trends Microbiol. 2005; 13: 320-327Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Often the initial evidence for a role for microtubules during establishment of infection stems largely from examining the effects of microtubule depolymerizing agents on the ability of incoming viruses to reach their site of replication and/or ensuing viral protein expression as they begin to replicate. While important, such observations provide only limited mechanistic insights into viral transport dynamics and regulation. More recently, however, the cytoplasmic movement of viruses, tagged with chemical fluorophores, began to be imaged in living cells using wide field fluorescence microscopy (Greber et al., 1997Greber U.F. Suomalainen M. Stidwill R.P. Boucke K. Ebersold M. Helenius A. The role of the nuclear pore complex in adenovirus DNA entry.EMBO J. 1997; 16: 5998-6007Crossref PubMed Scopus (176) Google Scholar, Leopold et al., 1998Leopold P.L. Ferris B. Grinberg I. Worgall S. Hackett N.R. Crystal R.G. Fluorescent virions—dynamic tracking of the pathway of adenoviral gene transfer vectors in living cells.Hum. Gene Ther. 1998; 9: 367-378Crossref PubMed Google Scholar, Leopold et al., 2000Leopold P.L. Kreitzer G. Miyazawa N. Rempel S. Pfister K.K. Rodriguez-Boulan E. Crystal R.G. Dynein- and microtubule-mediated translocation of adenovirus serotype 5 occurs after endosomal lysis.Hum. Gene Ther. 2000; 11: 151-165Crossref PubMed Scopus (157) Google Scholar, Suomalainen et al., 1999Suomalainen M. Nakano M.Y. Boucke K. Keller S. Stidwill R.P. Greber U.F. Microtubule-dependent minus and plus end-directed motilities are competing processes for nuclear targeting of adenovirus.J. Cell Biol. 1999; 144: 657-672Crossref PubMed Scopus (296) Google Scholar). Adenoviruses tagged with a few fluorophores on each of the 252 copies of the capsid hexon trimer were fully infectious and associated with microtubules (see Figure 1A). Imaging cells during the establishment of infection revealed that fluorescent capsids moved in a microtubule-dependent fashion both toward and away from the MTOC at speeds of ∼1–3 μm · s−1 (Suomalainen et al., 1999Suomalainen M. Nakano M.Y. Boucke K. Keller S. Stidwill R.P. Greber U.F. Microtubule-dependent minus and plus end-directed motilities are competing processes for nuclear targeting of adenovirus.J. Cell Biol. 1999; 144: 657-672Crossref PubMed Scopus (296) Google Scholar). The extent, directions, and velocities of these movements were variable over minutes but homogeneous over hours, resulting in accumulation of the virus at the center of the cell around 40 to 60 min postinfection. The behavior of adenovirus during the establishment of infection illustrates an important consideration when imaging the motility of viruses. Not only do infected cells have to be imaged for relatively long periods of time, but the sampling frequency needs to be sufficiently fast to be able to follow the highly variable bidirectional movements of individual virus particles. For example, while an imaging frequency of about one frame per min indicates that transcriptionally active HIV particles move along microtubules toward the nucleus (McDonald et al., 2002McDonald D. Vodicka M.A. Lucero G. Svitkina T.M. Borisy G.G. Emerman M. Hope T.J. Visualization of the intracellular behavior of HIV in living cells.J. Cell Biol. 2002; 159: 441-452Crossref PubMed Scopus (411) Google Scholar), it does not provide detailed information into the nature of these movements, as the dynein motor that is thought to provide the driving force normally moves with speeds in the order of μm · s−1 (King, 2003King S.M. Dynein motors: structure, mechanochemistry and regulation.in: Schliwa M. Molecular Motors. Wiley-VCH Verlag GmbH, Weinheim, Germany2003: 45-78Google Scholar, Mallik and Gross, 2004Mallik R. Gross S.P. Molecular motors: Strategies to get along.Curr. Biol. 2004; 14: R971-R982Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, Welte, 2004Welte M.A. Bidirectional transport along microtubules.Curr. Biol. 2004; 14: R525-R537Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). Reasons for low-frequency imaging include the problems of long exposures due to low signal to noise ratios and the accumulation of photo damage in the cell due to the toxicity of multiple illuminations. Both of these factors are a constant problem for cell biologists trying to follow rapid dynamic events in the μm · s−1 range. Fortunately, the presence of multiple copies of viral proteins that can be fluorescently tagged is conducive to increasing the fluorescence signal intensities of individual particles, allowing for a reduction in camera exposure times and an increase in acquisition frequency. This combined with recent advances in fluorophore stability, quantum yields, new GFP variants, and more sensitive cameras have made it relatively straightforward to image the motility of many different fluorescently tagged viruses with good temporal resolution. For example, it has become possible to image adeno-associated virus (AAV) type 2, a small parvovirus which can accept only a few fluorophores in its 20 nm sized capsid without loosing infectivity, at 25 frames per second, albeit for periods of only a few seconds (Seisenberger et al., 2001Seisenberger G. Ried M.U. Endress T. Buning H. Hallek M. Brauchle C. Real-time single-molecule imaging of the infection pathway of an adeno-associated virus.Science. 2001; 294: 1929-1932Crossref PubMed Scopus (482) Google Scholar). Imaging at these speeds has allowed extremely detailed analyses of virus movements during the infection, including determination of the maximal diffusion constants and the type of diffusion of individual viral trajectories (see Figure 4). Similar complex bidirectional microtubule-dependent movements have also been observed with influenza virus X-31, labeled with a fluorescent dye, which spontaneously inserts into the viral membrane (Lakadamyali et al., 2003Lakadamyali M. Rust M.J. Babcock H.P. Zhuang X. Visualizing infection of individual influenza viruses.Proc. Natl. Acad. Sci. USA. 2003; 100: 9280-9285Crossref PubMed Scopus (274) Google Scholar). It is clear from such studies that viruses are excellent subcellular probes which can be used to measure the physical properties of the cytoplasm in their surroundings. In recent years, analysis of the motility of viruses has benefited greatly from imaging recombinant viruses encoding GFP fusion proteins. In contrast to labeling viruses with chemical fluorophores, recombinant GFP fusions can give insights not only into movements during the establishment of infection but also those occurring throughout morphogenesis and the egress of newly assembled viruses from the infected cell. GFP has been successfully fused to the minor virion protein Vpr of HIV1 to visualize transcriptionally active particles moving bidirectionally along microtubules as well as incoming vaccinia virus cores during the establishment of infection (Carter et al., 2003Carter G.C. Rodger G. Murphy B.J. Law M. Krauss O. Hollinshead M. Smith G.L. Vaccinia virus cores are transported on microtubules.J. Gen. Virol. 2003; 84: 2443-2458Crossref PubMed Scopus (55) Google Scholar, McDonald et al., 2002McDonald D. Vodicka M.A. Lucero G. Svitkina T.M. Borisy G.G. Emerman M. Hope T.J. Visualization of the intracellular behavior of HIV in living cells.J. Cell Biol. 2002; 159: 441-452Crossref PubMed Scopus (411) Google Scholar). GFP fusions to tegument proteins, which are located between the lipid envelope and the capsid shell, have also been used to follow the complex bidirectional movements of herpes viruses during establishment of infection (Greber, 2005Greber U.F. Viral trafficking violations in axons—the herpes virus case.Proc. Natl. Acad. Sci. USA. 2005; 102: 5639-5640Crossref PubMed Scopus (5) Google Scholar, Sampaio et al., 2005Sampaio K.L. Cavignac Y. Stierhof Y.D. Sinzger C. Human cytomegalovirus labeled with green fluorescent protein for live analysis of intracellular particle movements.J. Virol. 2005; 79: 2754-2767Crossref PubMed Scopus (54) Google Scholar). Tegument proteins may not, however, be ideal reporters to track incoming particles associated with the viral genome, as they remain associated with the particles to varying degrees (Greber, 2005Greber U.F. Viral trafficking violations in axons—the herpes virus case.Proc. Natl. Acad. Sci. USA. 2005; 102: 5639-5640Crossref PubMed Scopus (5) Google Scholar). Fusion of GFP to VP26, a small outer capsid protein of HSV1, on the other hand, provides an authentic reporter for cytoplasmic transport of the viral genome during the establishment of infection (Dohner et al., 2005Dohner K. Nagel C.H. Sodeik B. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins.Trends Microbiol. 2005; 13: 320-327Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Analysis of a related herpes virus, pseudorabies virus (PRV) harboring VP26-GFP, revealed fast bidirectional microtubule-dependent motilities over a wide range of velocities as well as long periods of inactivity in the axon of chicken dorsal root ganglion neurons (Luxton et al., 2005Luxton G.W. Haverlock S. Coller K.E. Antinone S.E. Pincetic A. Smith G.A. Targeting of herpesvirus capsid transport in axons is coupled to association with specific sets of tegument proteins.Proc. Natl. Acad. Sci. USA. 2005; 102: 5832-5837Crossref PubMed Scopus (110) Google Scholar, Smith et al., 2001Smith G.A. Gross S.P. Enquist L.W. Herpesviruses use bidirectional fast-axonal transport to spread in sensory neurons.Proc. Natl. Acad. Sci. USA. 2001; 98: 3466-3470Crossref PubMed Scopus (155) Google Scholar, Smith et al., 2004Smith G.A. Pomeranz L. Gross S.P. Enquist L.W. Local modulation of plus-end transport targets herpesvirus entry and egress in sensory axons.Proc. Natl. Acad. Sci. USA. 2004; 101: 16034-16039Crossref PubMed Scopus (84) Google Scholar). During entry, PRV movements toward the MTOC in the cell body (retrograde) were favored over those to the cell periphery (anterograde), both in terms of velocity (average 1.17 versus 0.55 μm · s−1) and run length (average 7.38 versus 0.4 μm; Smith et al., 2004Smith G.A. Pomeranz L. Gross S.P. Enquist L.W. Local modulation of plus-end transport targets herpesvirus entry and egress in sensory axons.Proc. Natl. Acad. Sci. USA. 2004; 101: 16034-16039Crossref PubMed Scopus (84) Google Scholar). Interestingly, retrograde PRV motilities had similar average velocities and run lengths during both establishment of virus infection and later during egress of progeny, suggesting that they are both driven by single type of motor. Although it remains to be formally established, the dynein-dynactin complex is probably responsible for these retrograde PRV movements, as this motor complex is both recruited to and necessary for retrograde motility of HSV1 (Dohner et al., 2002Dohner K. Wolfstein A. Prank U. Echeverri C. Dujardin D. Vallee R. Sodeik B. Function of dynein and dynactin in herpes simplex virus capsid transport.Mol. Biol. Cell. 2002; 13: 2795-2809Crossref PubMed Scopus (161) Google Scholar, Sodeik et al., 1997Sodeik B. Ebersold M.W. Helenius A. Microtubule-mediated transport of incoming Herpes Simplex Virus 1 capsids to the nucleus.J. Cell Biol. 1997; 136: 1007-1021Crossref PubMed Scopus (400) Google Scholar). In contrast to retrograde movements, both the velocity and run length of anterograde-directed PRV motilities varied, depending on whether virus is undergoing entry or egress (Smith et al., 2004Smith G.A. Pomeranz L. Gross S.P. Enquist L.W. Local modulation of plus-end transport targets herpesvirus entry and egress in sensory axons.Proc. Natl. Acad. Sci. USA. 2004; 101: 16034-16039Crossref PubMed Scopus (84) Google Scholar). This suggests that overall the directionality of PRV motility is determined by the activity of the plus end-directed motor associated with the capsid. While the identity of the plus end-directed motor remains to be established, it appears that the viral tegument proteins play an important role in motility of the virus (Luxton et al., 2005Luxton G.W. Haverlock S. Coller K.E. Antinone S.E. Pincetic A. Smith G.A. Targeting of herpesvirus capsid transport in axons is coupled to association with specific sets of tegument proteins.Proc. Natl. Acad. Sci. USA. 2005; 102: 5832-5837Crossref PubMed Scopus (110) Google Scholar). By imaging recombinant PRV encoding VP26 tagged with mRFP, in combination with various GFP-tagged tegument proteins, the Smith group has shown that only VP1/2 and UL37 are associated with virus moving toward the cell body during entry. This observation suggests that the tegument proteins may play an important role in recruiting microtubule motors and/or modulating overall directionality of the virus. Consistent with this hypothesis, the same group has recently shown that microtubule-based egress of PRV is critically dependent on VP1/2 (Luxton et al., 2006Luxton G.W. Lee J.I. Haverlock-Moyns S. Schober J.M. Smith G.A. The pseudorabies virus VP1/2 tegument protein is required for intracellular capsid transport.J. Virol. 2006; 80: 201-209Crossref PubMed Scopus (64) Google Scholar). Although extremely powerful, there are some caveats to using GFP to visualize virus particle movements. One limitation is that it may not be possible to make recombinants for all virus types, including hepatitis B and C viruses or icosahedral nonenveloped viruses, which have a tightly confined capsid geometry and limited internal space. Another possibility is that the GFP tag may impair viral infectivity. Thus, it is always crucial to ensure that the recombinant virus behaves as closely to the wild-type progenitor as possible in terms of infectivity, assembly kinetics, and viral release. Such potential difficulties may sometimes be overcome by choosing specific GFP insertion sites within capsid proteins, as demonstrated recently for the small parvovirus AAV type 2 (Lux et al., 2005Lux K. Goerlitz N. Schlemminger S. Perabo L. Goldnau D. Endell J. Leike K. Kofler D.M. Finke S. Hallek M. Buning H. Green fluorescent protein-tagged adeno-associated virus particles allow the study of cytosolic and nuclear trafficking.J. Virol. 2005; 79: 11776-11787Crossref PubMed Scopus (59) Google Scholar, Warrington et al., 2004Warrington Jr., K.H. Gorbatyuk O.S. Harrison J.K. Opie S.R. Zolotukhin S. Muzyczka N. Adeno-associated virus type 2 VP2 capsid protein is nonessential and can tolerate large peptide insertions at its N terminus.J. Virol. 2004; 78: 6595-6609Crossref PubMed Scopus (77) Google Scholar). Alternatively, one may follow the nucleic acid with molecular beacons, as recently shown for poliovirus RNA in live cells (Cui et al., 2005Cui Z.Q. Zhang Z.P. Zhang X.E. Wen J.K. Zhou Y.F. Xie W.H. Visualizing the dynamic behavior of poliovirus plus-strand RNA in living host cells.Nucleic Acids Res. 2005; 33: 3245-3252Crossref PubMed Scopus (32) Google Scholar). HIV Gag has also been imaged in live cells using a FLASH approach (Rudner et al., 2005Rudner L. Nydegger S. Coren L.V. Nagashima K. Thali M. Ott D.E. Dynamic fluorescent imaging of human immunodeficiency virus type 1 gag in live cells by biarsenical labeling.J. Virol. 2005; 79: 4055-4065Crossref PubMed Scopus (77) Google Scholar), which relies on the generation of a fluorescent signal when membrane-permeable biarsenical compounds associate with a tetracysteine tag introduced into the protein. To date, the only motor implicated in inward microtubule-based virus movements in animal cells is the minus end-directed motor cytoplasmic dynein (Figure 2; Dohner et al., 2005Dohner K. Nagel C.H. Sodeik B. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins.Trends Microbiol. 2005; 13: 320-327Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). In animal cells, the dynein-dynactin motor complex is required for many functions, including transport of mRNA, intermediate filament and centrosomal proteins, mitotic spindle assembly, kinetochore functions, and movement of signaling proteins (King, 2003King S.M. Dynein motors: structure, mechanochemistry and regulation.in: Schliwa M. Molecular Motors. Wiley-VCH Verlag GmbH, Weinheim, Germany2003: 45-78Google Scholar, Mallik and Gross, 2004Mallik R. Gross S.P. Molecular motors: Strategies to get along.Curr. Biol. 2004; 14: R971-R982Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, Schroer, 2004Schroer T.A. Dynactin.Annu. Rev. Cell Dev. Biol. 2004; 20: 759-779Crossref PubMed Scopus (330) Google Scholar, Vallee et al., 2004Vallee R.B. Williams J.C. Varma D. Barnhart L.E. Dynein: an ancient motor protein involved in multiple modes of transport.J. Neurobiol. 2004; 58: 189-200Crossref PubMed Scopus (250) Google Scholar). Nevertheless, dynein-dynactin components have been elusive and are not readily visualized on cellular cargoes. In contrast, components of the dynein motor complex have been observed on a number of incoming viruses, including HSV1, HIV1, canine parvovirus, and rabies virus, next to microtubules (Dohner et al., 2005Dohner K. Nagel C.H. Sodeik B. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins.Trends Microbiol. 2005; 13: 320-327Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). The dynein-dynactin complex has also been shown to bind to adenovirus and enhances its association with microtubules in vitro (Kelkar et al., 2004Kelkar S.A. Pfister K.K. Crystal R.G. Leopold P.L. Cytoplasmic dyne" @default.
• W2054165784 created "2016-06-24" @default.
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• W2054165784 date "2006-02-01" @default.
• W2054165784 modified "2023-10-12" @default.
• W2054165784 title "A Superhighway to Virus Infection" @default.
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