CMLS, Cell. Mol. Life Sci. 59 (2002) 608–626 1420-682X/02/040608-19 $ 1.50 + 0.20/0 © Birkhäuser Verlag, Basel, 2002 CMLS Cellular and Molecular Life Sciences Review Signalling in viral entry U.F. Greber University of Zürich, Institute of Zoology, Winterthurerstrasse 190, 8057 Zürich (Switzerland), Fax: +41 1 635 6822, e-mail: [email protected] Received 13 September 2001; received after revision 23 October 2001; accepted 16 November 2001 Abstract. Viral infections are serious battles between tracellular signals triggering specific cellular reactions. pathogens and hosts. They can result in cell death, elimi- Responses by cells include stimulation of innate and nation of the virus or latent infection keeping both cells adaptive immunity, growth, proliferation, survival and and pathogens alive. The outcome of an infection is often apoptosis. In addition, virus-activated cell signalling determined by cell signalling. Viruses deliver genomes boosts viral entry and gene delivery, as recently shown for and proteins with signalling potential into target cells and adenoviruses and adeno-associated viruses. This review thereby alter the metabolism of the host. Virus interac- illustrates that multiple activation of host cells during vi- tions with cell surface receptors can elicit two types of ral entry profoundly impacts the elaborate relationship signals, conformational changes of viral particles, and in- between hosts and viral pathogens. Key words. Entry; receptor; signal transduction; trafficking; virus infection. Introduction vaccination programmes have led to the prevention of some virus-caused diseases such as poliomyelitis, he- Viruses are tiny and are largely dependent on their hosts patitis B, virus-associated chronic liver disease and can- for survival. They propagate by replicating inside their cer of the liver [5]. On the other hand, the simplicity of host’s cells. Viruses carry a minimal amount of informa- viruses has made them useful instruments for the study tion with them. A thin protein coat wraps around a small of genetics, cell and structural biology, immunology and bag of genes. Unlike cellular genomes, which are pro- biochemistry [6]. Studies of viruses have also made ma- tected and regulated by a variety of different polypep- jor contributions to our understanding of principal cell tides, viral genomes encode only a few coat and regula- functions, including the structure of DNA, genomic reg- tory proteins [1]. Viruses use their proteins repetitively to ulation, transcription, processing and transport of RNA, build up regular geometrical ‘capsids’ [2], demonstrating protein trafficking and evolution [3, 7]. Viral research that they have evolved effective use of their genetic and has even contradicted a long-standing dogma of molecu- structural outfit [3]. lar biology through the discovery that RNA-containing Despite their apparent simplicity, viruses attract serious retroviruses reverse the normal flow of genetic informa- concern for the misery and illness they cause [4]. Most tion by using an enzyme, reverse transcriptase, to tran- people regard viruses as uninvited and opportunistic scribe single-stranded RNA into double-stranded DNA guests which struggle with their host in an effort to repli- [8, 9]. In contrast to the standard view, viruses might cate and spread their genetic material. Virally transmit- even provide essential functions for the host. One hy- ted diseases range from the common cold to numerous pothesis proposes that endogenous retroviruses (ERVs) forms of immunodeficiencies and cancer. Large-scale of mammals locally suppress a cellular immune response CMLS, Cell. Mol. Life Sci. Vol. 59, 2002 Review Article 609 against the growing placental tissue, thus supporting ac- ceptance of the allogeneic embryo in the mother [10]. A recent report goes further to suggest that a cellular gene captured by a human ERV serves an important function in the generation of trophoblast tissue by stimulating cell-cell fusion [11]. Another attractive speculation is that viruslike transposons are at the evolutionary origin of immunoglobulin heavy chain and the T-cell-receptor b-chain assembly in immature B and T cells, respectively [12]. But how does it happen that viruses utilize their targets so effectively, given that host benefits from viral infections seem to be scarce? The short answer to this question is that viruses are extremely well adapted to their hosts. A major part of this adaptation is that viruses manipulate host cell signalling. Biochemical and genomic analyses in the last decades have revealed that viruses harbor both genetic and nongenetic information with signalling po- tential [3, 13]. At least three principal mechanisms ac- count for viral activation of cells (fig. 1). The delivery of signalling genes is probably the best-studied mechanism, whereas deposition of signalling proteins by incoming vi- ral particles and activation of surface receptors are re- ceiving increasing attention. This review aims to illustrate how viruses utilize signalling, with particular emphasis on how the process of cell entry by viruses can depend on signalling. A detailed review of viral structures and other aspects of viral life cycles is available elsewhere (for re- view, see e.g., [14–18]). Delivery of signalling genes and proteins The advent of high-resolution electron microscopy and reproducible cell-culture technology about 50 years ago enabled the tracking of intracellular viruses and viral genomes during infections. Sequencing of viral genomes Figure 1. Three modes of viral activations of host cells. The most and inventory of viral proteins have revealed that the prevailing activation mode occurs by viral gene expressions (panel genomes of certain retroviruses, for example, contain A). Incoming viruses deliver their genes to subcellular replication sites (steps 1 and 2) and from there drive the transcription of viral cellular genes of crucial signalling function that can lead genes encoding intracellular (steps 3a and 4a) and extracellular sig- to cell transformation and oncogenesis (fig. 1A). In fact, nalling factors (steps 3b and 4b). Panel B: The second mode of sig- the first oncogene discovered was the cellular nonrecep- nalling is a delivery of proteins or mRNAs by incoming viruses tor tyrosine kinase Src, pirated by the chicken Rous sar- (step 1). These molecules can interfere with cell signalling (steps 2 and 3). Panel C: During entry, many incoming viruses recruit a pri- coma virus [19]. Many other cell-derived oncogenes mary receptor (step 1) and/or a secondary receptor with signalling have since been identified in transforming retroviruses. functions (step 2) and thus lead to cell activation (step 3). The corresponding cell-owned protooncogenes are typi- cally involved in mitogenic signalling and include pep- tide growth factors, growth factor receptors, protein and lipid kinases, G proteins and transcription factors (re- tivity (reviewed in [24]). For example, the multifunc- viewed in [20–23]). Viral genomes also contain genes to tional cytokine tumor necrosis factor (TNF-a) is pro- counteract host defence mechanisms. They are necessary duced in activated monocytes and macrophages and ac- for viral survival in an infected organism, since acute in- tivates caspases that lead to apoptosis of infected cells. fections are invariably countered by an innate immune Viral countermeasures include the downregulation of response, mounting type I and type II interferons (IFNs), immune modulating proteins, inhibition of apoptosis, cytokines and increased levels of natural killer cell ac- dysregulation of cytokine production and even destruc- 610 U.F. Greber Signalling in viral entry tion of immune cells (for reviews, see [25, 26]). Aden- Receptors for viral attachment oviruses, for example, counteract the lytic action of TNF-a by a variety of proteins encoded in the E3 region Much work has been devoted to the identification of viral [27]. Poxviruses produce a number of soluble cytokine receptors. The receptor is of central importance for infec- receptors that act as decoy molecules to neutralize cy- tion and typically serves to enrich virus particles on target tokines [28]. In addition, herpes- and poxviruses encode cells. Viruses have selected their primary receptors on the seven transmembrane G-protein-coupled receptors basis of availability and accessibility, functional coupling (GPCRs), presumably derived from the host chemokine to coreceptors and perhaps also downregulation to prevent system (for recent reviews, see [29, 30]). Although most superinfection and support viral release (reviewed in [40]). of these receptors are still orphan receptors, the human Members from one virus family can choose a large variety herpesvirus 8 protein ORF74 seems to be positively of receptors, as exemplified in a recent survey of retroviral modulated by angiogenic chemokines and is associated receptors (reviewed in [41]). Broad availability is a promi- with cell transformation through phospholipase C and nent feature of large glycosamino-glycans, present in he- mitogen-activated protein kinase (MAPK) signalling paran sulphate and chondroitin sulphate proteoglycans. pathways. It is likely that ORF74 has a major role in Glycosamino-glycans have been reported to serve as pri- HHV-8-associated Kaposi’s sarcomas. This example un- mary attachment sites for HSV-1 [42, 43], CMV [44], derscores the principle that viruses take control of cell adeno-associated virus-2 (AAV-2) [45] and for the sub- proliferation by pirating and