- freely available
Viruses 2013, 5(2), 528-549; doi:10.3390/v5020528
Published: 31 January 2013
Abstract: The Arenaviridae is a diverse and growing family of viruses that includes several agents responsible for important human diseases. Despite the importance of this family for public health, particularly in Africa and South America, much of its biology remains poorly understood. However, in recent years significant progress has been made in this regard, particularly relating to the formation and release of new enveloped virions, which is an essential step in the viral lifecycle. While this process is mediated chiefly by the viral matrix protein Z, recent evidence suggests that for some viruses the nucleoprotein (NP) is also required to enhance the budding process. Here we highlight and compare the distinct budding mechanisms of different arenaviruses, concentrating on the role of the matrix protein Z, its known late domain sequences, and the involvement of cellular endosomal sorting complex required for transport (ESCRT) pathway components. Finally we address the recently described roles for the nucleoprotein NP in budding and ribonucleoprotein complex (RNP) incorporation, as well as discussing possible mechanisms related to its involvement.
The Arenaviridae is a diverse and growing family of viruses, presently containing 24 recognized species  and several other proposed species [2,3,4,5,6,7,8,9,10,11,12,13,14], including many of considerable significance to human health (Table 1). Based on their antigenicity and phylogenetic analysis, and underscored by their geographical distribution, arenaviruses can be taxonomically divided into the Old World arenavirus (OWAV) and the New World arenavirus (NWAV) serocomplexes .
Among the OWAVs, both Lassa virus (LASV) and the recently identified Lujo virus (LUJV) are capable of causing hemorrhagic fever (HF) [7,15]. While the number of Lujo cases thus far reported has been minimal, LASV represents a major public health problem in Western Africa, where it has been estimated to cause 300,000–500,000 cases annually, resulting in 3,000–5,000 deaths . In addition, while lymphocytic choriomeningitis virus (LCMV) usually causes asymptomatic illness in healthy individuals, in some cases it is known to cause aseptic meningitis, and while fatalities are rare, vertical transmission during pregnancy can have severe deleterious effects on the fetus. Further, severe infection has been reported in a few cases involving transplant patients , indicating that in immunocompromised individuals LCMV infection may pose additional risks. The remaining members of this serocomplex do not appear to be significant human pathogens.
In the case of the NWAV serocomplex, viruses can be further divided into three clades (A, B and C) based on phylogenetic relationships , although recombination events between these clades are also possible. This is the case with Whitewater Arroyo virus (WWAV) as well as other North American arenaviruses, which are clade A/B recombinants . Interestingly, this separation into distinct clades also corresponds to differences in receptor usage and disease phenotype . The NWAVs are responsible for at least five distinct HFs [8,18], collectively referred to as South American Hemorrhagic Fevers (SAHFs), which are caused by Junìn (JUNV), Machupo (MACV), Chapare (CHPV), Guanarito (GTOV) and Sabiá (SABV) viruses. All of these viruses are members of the Clade B NWAVs and have been shown to use the Transferrin alpha receptor (TfR1) for entry into target cells [20,21]. While non-pathogenic Clade B members use the TfR1 orthologs of various other mammalian species , some evidence also exists that they can infect cells efficiently in a completely TfR1-independent manner . NWAVs of Clade C have been shown to use α-dystroglycan as a receptor , similar to OWAVs .
In total arenaviruses cause at least seven distinct hemorrhagic fevers, making them the largest family of HF-causing viruses currently known. In addition, both the NWAVs and OWAVs contain a number of human apathogenic strains, which are in some cases quite closely related to the agents of HF disease. The basis for these marked differences in virulence among genetically closely related viruses remains unknown. Similarly, despite their significance for public health, many details of the arenavirus lifecycle, including the pathways used for virus morphogenesis and budding, remain poorly understood. However, in recent years significant progress has been made in this area and has revealed interesting commonalities in the mechanisms used by the various arenaviruses but also striking differences that remain to be fully explained from a mechanistic stand-point. Here we attempt to summarize the current state of our knowledge, including recent findings, in the field of arenavirus morphogenesis and budding.
|Table 1. Viruses of the family Arenaviridae, their geographic distribution, reservoirs andassociated human diseases.|
|Old World Arenviruses||Dandenong virus*||Yugoslavia (?)|
|Unknown||Febrile illness with encephalopathy (transplant-related)|
|Gbagroube virus*||Côte d'Ivoire||Mus (Nannomys) setulosus||None known|
|Ippy virus||Central African Republic||Arvicanthus spp.||None known|
|Lassa virus||Western Africa||Mastomys natalensis||Febrile illness, hemorrhagic fever in severe cases|
|Lymphocytic Choriomeningitis virus||Worldwide||Mus musculus||Febrile illness, aseptic meningitis in severe cases|
|Lujo virus||Zambia||Unknown||Hemorrhagic fever|
|Luna virus*||Zambia||Mastomys natalensis||None known|
|Kodoko virus*||Guinea||Mus (Nannomys) minutoides||None known|
|Menekre virus*||Côte d'Ivoire||Hylomyscus spp.||None known|
|Merino Walk virus*||South Africa||Myotomis unisulcatus||None known|
|Mobala virus||Central African Republic||Praomys jacksoni||None known|
|Mopeia virus||Mozambique||Mastomys natalensis||None known|
|Morogoro virus*||Tanzania||Mastomys spp.||None known|
|New World Arenaviruses||Allpahuayo virus||Peru||Oecomys spp.||None known|
|Amapari virus||Brazil||Oryzomys gaeldi Neacomys guianae||None known|
|Bear Canyon virus||USA||Peromyscus californicus||None known|
|Big Brushy Tank virus*||USA||Neotoma albigula||None known|
|Catarina virus*||USA||Neotoma micropus||None known|
|Chapare virus||Bolivia||Unknown||Hemorrhagic fever|
|Cupixi virus||Brazil||Oryzomys spp.||None known|
|Flexal virus||Brazil||Oryzomys spp.||Febrile illness(Lab-acquired)|
|Guanarito virus||Venezuela||Zygodontomys brevicauda||Hemorrhagic fever|
|Junín virus||Argentina||Calomys musculinus||Hemorrhagic fever|
|Latino virus||Bolivia||Calomys callosus||None known|
|Machupo virus||Bolivia||Calomys callosus||Hemorrhagic fever|
|Oliveros virus||Argentina||Bolomys spp.||None known|
|Paraná virus||Paraguay||Oryzomys buccinatus||None known|
|Pichinde virus||Columbia||Oryzomys albigularis||None known|
|Pinhal virus||Brazil||Calomys tener||None known|
|Pirital virus||Venezuela||Sigmodon alstoni||None known|
|Real de Catorce virus*||Mexico||Neotoma leucodon||None known|
|Sabiá virus||Brazil||Unknown||Hemorrhagic fever|
|Skinner Tank virus*||USA||Neotoma mexicana||None known|
|Tacaribe virus||Trinidad||Artibeus spp. (bat)||Possible febrile illness (Lab-acquired)|
|Tamiami virus||USA||Sigmodon hispidus||None known|
|Tonto Creek virus||USA||Neotoma albigula||None known|
|Whitewater Arroyo virus||USA||Neotoma albigula||Possible hemorrhagic fever|
* proposed species not yet classified by the ICTV
3. Virus Budding and Host Cell Sorting
The host cell membrane represents a significant barrier to the egress of newly formed or forming viral particles. In order to overcome this physical barrier many viruses have evolved to take advantage of host cell sorting pathways, in particular those directing vesicle formation into multi-vesicular bodies (MVBs). Thus for many enveloped viruses, including arenaviruses, it has been shown that they recruit the endosomal sorting complex required for transport (ESCRT) machinery of the host cell to facilitate their release [55,56]. However, there are also viruses whose release appears to be completely independent of the cellular ESCRT complexes [55,56]. The ability of viruses to subvert the cellular ESCRT machinery to drive viral budding likely derives from the fact that both of these processes involve budding being directed away from the cytoplasm, either into MVBs, in the case of vesicular budding, or into the extracellular space, in the case of virus budding.
In the uninfected host cell the ESCRT-system is involved in MVB vesicle formation and cytokinesis. It consists of six complexes (ESCRT-0, -I, -II, -III, Alix/AIP1 and Vps4) that are recruited sequentially to the sites of membrane remodelling and fission. While ESCRT-0 binds to and accumulates ubiquitinated cargo for delivery into the MVBs, the ESCRT-I and ESCRT-II complexes are recruited and co-assemble on the membrane to drive bud formation. ESCRT-III, which is responsible for final membrane scission, is recruited by binding to ESCRT-I and/or Alix/AIP1, which connects these complexes. Finally the AAA-type ATPase Vps4 mediates disassembly of the complex and its subsequent recycling . During virus infection some of these ESCRT-complexes are targeted by the viral matrix protein, and in some cases also other viral proteins, to the sites of viral budding where they mediate the budding process of membrane enveloped particles using an analogous mechanism.
For many enveloped viruses it has been shown that the self-budding activity of their matrix protein is functionally dependent on the presence of late domain motifs within their sequences (reviewed in [56,57,58]). To date several late domain sequences have been reported (Table 2), with the tetrapeptide motifs PPxY, PT/SAP, and YxxL (x = any amino acid) appearing to be the most prevalent . However, more recently θPxV (θ = hydrophobic amino acid) was identified as the functional late-domain sequence in simian virus 5 (SV5)  and although its interaction partner remains unknown, its identification serves to reinforce the possibility that other as yet unidentified late-domain motifs may also exist.
|Table 2. Late-domain motif usage among different virus families.|
|Motif||Virus families using this motif (interacting proteins)||References|
|YxxL||Arenaviridae (NP, Z)|
Paramyxoviridae (C, M)
Filoviridae (NP, VP40)
X indicates any amino acid, while θ indicates hydrophobic amino acids.* not important for budding
Late-domain motifs promote viral budding by mediating the interaction of viral proteins with components of the cellular ESCRT-machinery or ESCRT-associated ubiquitin ligases, an observation that appears to hold true for a variety of virus families with which these studies have been conducted. The viral PT/SAP motif has been shown to recruit the ubiquitin-binding ESCRT-I-component tumor susceptibility gene 101 (Tsg101) to initiate viral budding [51,66,68,69,71]. This interaction occurs through an N-terminal ubiquitin E2 variant (UEV) domain, which is normally responsible for interaction of the ESCRT-I complex with ESCRT-0 and ubiquitinated cargo  (Figure 3). A C-terminally located PTAP motif in Tsg101 is also capable of binding to the UEV domain and in doing so blocks access of additional molecules, thus serving an auto-regulatory function . For the PPxY motif, Nedd4-like ubiquitin ligases have been identified as an interaction partner [66,73,74] with interaction taking place between the PPxY tetrapeptide and a series of WW-domains in Nedd4-like proteins (Figure 3). Finally the MVB component Alix/AIP1 can also be recruited by viral matrix proteins and this occurs through binding of the YxxL motif to the V domain [61,64,75,76] (Figure 3). In addition Alix/A1P1 contains a C-terminal PSAP, which mediates its interaction with Tsg101, again through the UEV domain of Tsg101, and a Bro1 domain, which is responsible for interaction with CHMP4, an important ESCRT-III component .
6. The Budding Pathway as a Potential Target for Therapeutics
Arenaviruses are serious public health concerns in many parts of the world and thus the development of vaccines and anti-viral therapies remains an important priority. An understanding of the exact mechanisms used for virus morphogenesis and release will help to offer new possibilities to combat viral infection by targeting these pathways. Such targets could include both the interactions among viral proteins (i.e. Z-NP interactions) and interactions between viral and host cell components. Emphasizing this potential, tetherin has recently been identified as a novel antiviral factor that is able to inhibit Z-mediated release of arenaviruses [86,87]. Tetherin or BST-2 (bone marrow stromal antigen 2) is an IFN-inducible membrane protein that was first shown to inhibit the release of HIV-1 [88,89]. For arenaviruses it was shown that the overexpression of tetherin reduced MOPV and LASV VLP production, as well as production of LASV virions . Even if the exact mechanism by which tetherin antagonizes arenavirus budding remains unclear, the identification of this protein as an inhibitor of LASV Z-mediated budding  reinforces the importance of the budding pathway as a potential target for novel therapeutics.
In addition to the proline-rich and YxxL-type late-domains found within the matrix protein, N-terminal myristoylation also plays a decisive role in viral budding. This post-translational modification takes place at a glycine residue at position 2 (G2) in the Z protein sequence and is universally conserved among all arenaviruses (Figure 4). The myristoylation of Z is necessary for its binding to the plasma membrane, which is the site of arenavirus budding, and thus is also required for efficient viral release. For the OWAVs LASV, LCMV and MOPV, as well as for the NWAVs JUNV and TCRV it was shown that inhibition of myristoylation, either by mutation of the G2 residue or the use of an inhibitor, clearly represses Z-mediated budding [49,53,60,77,78], thus presenting another cellular pathway that could potentially be exploited by intervention strategies.
Finally, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in a variety of cellular processes , has also been shown to be important in the lifecycle of diverse viruses, including arenaviruses [91,92,93,94]. In the case of LCMV it was shown that inhibition of PI3K/Akt signalling, while not having an influence on viral entry, resulted in reduced viral RNA synthesis and the inhibition of viral budding . As the PI3K/Akt pathway is involved in cellular vesicular trafficking, it has been suggested that the associated signalling might be needed for assembly of the ESCRT-complexes and, therefore, that an inhibition of this pathway might disrupt the budding process . It has also been further speculated that the PI3K/Akt pathway might be involved in phosphorylation of LCMV and LASV Z . However, despite these intriguing suggestions the exact mechanism by which the PI3K/Akt pathway contributes to arenavirus budding remains to be determined.
The formation of progeny virus particles and their release is an essential step in the lifecycle of a virus. In recent years significant progress has been made in the field of arenavirus morphogenesis and budding. The findings have revealed many commonalities in the budding mechanisms used by different arenaviruses, but also striking differences.
The matrix protein Z of arenaviruses has been shown to provide the driving force for budding, an activity that depends on various distinct motifs that have been identified within the protein. Among these are an N-terminal myristoylation at glycine 2 (G2) of Z, which mediates binding of Z to the host cell plasma membrane, and various late domains (YxxL, PPxY and/or PT/SAP). These late domains are responsible for the recruitment of different components of the cellular ESCRT-machinery, normally involved in vesicle formation, to the budding-site where they initiate the release of membrane enveloped virions from the infected host cell (Figure 6). While the arrangement of late-domains in Z differs between the individual arenavirus species, interaction with components within the ESCRT-dependent budding pathway appears to be universal. While NWAVs mostly contain a single PT/SAP motif, OWAVs generally contain either a PPxY motif alone or both a PPxY and a PT/SAP motif at the C-terminus of the Z protein. The PT/SAP motif has been shown to mediate interaction with and recruitment of the ESCRT-I component Tsg101, however, an interaction partner for the PPxY motif of Z has yet to be identified. While interaction of the PPxY motif with a Nedd4-like ubiquitin ligase is likely, in the case of LASV, interaction with Nedd4 itself has been shown not to occur. TCRV Z appears to present a unique case in that it does not contain any proline-rich late domain at all. However, it still functions as a matrix protein. Perhaps due to this lack of any proline-rich late domains the ESCRT-dependent release of TCRV Z-induced particles is strongly enhanced by the presence of NP, raising the question of whether the recruitment of additional ESCRT-components might be assisted by late domains within NP (Figure 6). Such a mechanism appears, thus far, to be unique among the arenaviruses. Finally, recent studies of MOPV have revealed that the ESCRT-machinery might also facilitate recruitment of the viral nucleocapsid to the site of budding and its subsequent incorporation into particles through an interaction between Alix/AIP1 and both Z and NP. A similar mechanism also seems likely for TCRV; however, it remains unclear how OWAVs that lack a YxxL domain, and thus likely the ability to recruit Alix-AIP1, are able to incorporate their RNPs.
In summary, the current data reveal a budding mechanism for arenaviruses that is ESCRT-dependent, but involves a variety of different players depending on the virus species examined. Clearly there are also a number of unknowns and issues that need to be further investigated, especially given the significance of arenaviruses for public health, as a better understanding of the mechanisms and pathways used for virus morphogenesis might offer new possibilities for the development of antiviral therapies to combat arenavirus infection.
The authors are very grateful to Stephen Becker (Philipps Universität Marburg) for helpful discussion and Olga Dolnik (Philipps Universität Marburg) for conceptual assistance with some of the figures. This work was funded by grants of the Jürgen Manchot Stiftung (S.W.) and the Canadian Institutes of Health Research (A.G.) as well being funded in part by the Philipps Universität Marburg and the Division of Intramural Research, NIAID, NIH.
Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the NIH or the Philipps Universität Marburg.
Conflict of Interest
The authors declare no conflict of interest.
References and Notes
- Salvato, M.S.; Clegg, J.C.S.; Buchmeier, M.J.; Charrel, R.N.; Gonzalez, J.P.; Lukashevich, I.S.; Peters, C.J.; Romanowski, V. Family arenaviridae. In: Virus taxonomy: Classification and nomenclature of viruses: Ninth report of the international committee on taxonomy of viruses. Academic Press, Elsevier 2012, 715–723.
- Charrel, R.N.; de Lamballerie, X.; Emonet, S. Phylogeny of the genus arenavirus. Curr. Opin. Microbiol. 2008, 11, 362–368, doi:10.1016/j.mib.2008.06.001.
- Ishii, A.; Thomas, Y.; Moonga, L.; Nakamura, I.; Ohnuma, A.; Hang'ombe, B.; Takada, A.; Mweene, A.; Sawa, H. Novel arenavirus, zambia. Emerg Infect Dis 2011, 17, 1921–1924, doi:10.3201/eid1710.10452.
- Inizan, C.C.; Cajimat, M.N.; Milazzo, M.L.; Barragan-Gomez, A.; Bradley, R.D.; Fulhorst, C.F. Genetic evidence for a tacaribe serocomplex virus, mexico. Emerg. Infect. Dis. 2010, 16, 1007–1010.
- Gunther, S.; Hoofd, G.; Charrel, R.; Roser, C.; Becker-Ziaja, B.; Lloyd, G.; Sabuni, C.; Verhagen, R.; van der Groen, G.; Kennis, J.; et al. Mopeia virus-related arenavirus in natal multimammate mice, morogoro, tanzania. Emerg. Infect. Dis. 2009, 15, 2008–2012.
- Palacios, G.; Savji, N.; Hui, J.; Travassos da Rosa, A.; Popov, V.; Briese, T.; Tesh, R.; Lipkin, W.I. Genomic and phylogenetic characterization of merino walk virus, a novel arenavirus isolated in south africa. J. Gen. Virol. 2010, 91, 1315–1324, doi:10.1099/vir.0.017798-0.
- Briese, T.; Paweska, J.T.; McMullan, L.K.; Hutchison, S.K.; Street, C.; Palacios, G.; Khristova, M.L.; Weyer, J.; Swanepoel, R.; Egholm, M.; et al. Genetic detection and characterization of lujo virus, a new hemorrhagic fever-associated arenavirus from southern africa. PLoS Pathog. 2009, 5, e1000455.
- Delgado, S.; Erickson, B.R.; Agudo, R.; Blair, P.J.; Vallejo, E.; Albarino, C.G.; Vargas, J.; Comer, J.A.; Rollin, P.E.; Ksiazek, T.G.; et al. Chapare virus, a newly discovered arenavirus isolated from a fatal hemorrhagic fever case in bolivia. PLoS Pathog. 2008, 4, e1000047, doi:10.1371/journal.ppat.1000047.
- Lecompte, E.; ter Meulen, J.; Emonet, S.; Daffis, S.; Charrel, R.N. Genetic identification of kodoko virus, a novel arenavirus of the african pigmy mouse (mus nannomys minutoides) in west africa. Virology 2007, 364, 178–183, doi:10.1016/j.virol.2007.02.008.
- Coulibaly-N'Golo, D.; Allali, B.; Kouassi, S.K.; Fichet-Calvet, E.; Becker-Ziaja, B.; Rieger, T.; Olschlager, S.; Dosso, H.; Denys, C.; Ter Meulen, J.; et al. Novel arenavirus sequences in hylomyscus sp. And mus (nannomys) setulosus from cote d'ivoire: Implications for evolution of arenaviruses in africa. PLoS One 2011, 6, e20893.
- Cajimat, M.N.; Milazzo, M.L.; Borchert, J.N.; Abbott, K.D.; Bradley, R.D.; Fulhorst, C.F. Diversity among tacaribe serocomplex viruses (family arenaviridae) naturally associated with the mexican woodrat (neotoma mexicana). Virus Res. 2008, 133, 211–217.
- Milazzo, M.L.; Cajimat, M.N.; Haynie, M.L.; Abbott, K.D.; Bradley, R.D.; Fulhorst, C.F. Diversity among tacaribe serocomplex viruses (family arenaviridae) naturally associated with the white-throated woodrat (neotoma albigula) in the southwestern united states. Vector Borne Zoonotic Dis. 2008, 8, 523–540, doi:10.1089/vbz.2007.0239.
- Cajimat, M.N.; Milazzo, M.L.; Bradley, R.D.; Fulhorst, C.F. Catarina virus, an arenaviral species principally associated with neotoma micropus (southern plains woodrat) in texas. Am. J. Trop. Med. Hyg. 2007, 77, 732–736.
- Palacios, G.; Druce, J.; Du, L.; Tran, T.; Birch, C.; Briese, T.; Conlan, S.; Quan, P.L.; Hui, J.; Marshall, J.; et al. A new arenavirus in a cluster of fatal transplant-associated diseases. N. Engl. J. Med. 2008, 358, 991–998, doi:10.1056/NEJMoa073785.
- Gunther, S.; Lenz, O. Lassa virus. Crit. Rev. Clin. Lab. Sci. 2004, 41, 339–390, doi:10.1080/10408360490497456.
- McCormick, J.B.; Webb, P.A.; Krebs, J.W.; Johnson, K.M.; Smith, E.S. A prospective study of the epidemiology and ecology of lassa fever. J. Infect. Dis. 1987, 155, 437–444.
- Fischer, S.A.; Graham, M.B.; Kuehnert, M.J.; Kotton, C.N.; Srinivasan, A.; Marty, F.M.; Comer, J.A.; Guarner, J.; Paddock, C.D.; DeMeo, D.L.; et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N. Engl. J. Med. 2006, 354, 2235–2249.
- Charrel, R.N.; de Lamballerie, X. Arenaviruses other than lassa virus. Antiviral Res. 2003, 57, 89–100, doi:10.1016/S0166-3542(02)00202-4.
- Charrel, R.N.; de Lamballerie, X.; Fulhorst, C.F. The whitewater arroyo virus: Natural evidence for genetic recombination among tacaribe serocomplex viruses (family arenaviridae). Virology 2001, 283, 161–166.
- Radoshitzky, S.R.; Abraham, J.; Spiropoulou, C.F.; Kuhn, J.H.; Nguyen, D.; Li, W.; Nagel, J.; Schmidt, P.J.; Nunberg, J.H.; Andrews, N.C.; et al. Transferrin receptor 1 is a cellular receptor for new world haemorrhagic fever arenaviruses. Nature 2007, 446, 92–96.
- Helguera, G.; Jemielity, S.; Abraham, J.; Cordo, S.M.; Martinez, M.G.; Rodriguez, J.A.; Bregni, C.; Wang, J.J.; Farzan, M.; Penichet, M.L.; et al. An antibody recognizing the apical domain of human transferrin receptor 1 efficiently inhibits the entry of all new world hemorrhagic fever arenaviruses. J. Virol. 2012, 86, 4024–4028.
- Abraham, J.; Kwong, J.A.; Albarino, C.G.; Lu, J.G.; Radoshitzky, S.R.; Salazar-Bravo, J.; Farzan, M.; Spiropoulou, C.F.; Choe, H. Host-species transferrin receptor 1 orthologs are cellular receptors for nonpathogenic new world clade b arenaviruses. PLoS Pathog. 2009, 5, e1000358.
- Flanagan, M.L.; Oldenburg, J.; Reignier, T.; Holt, N.; Hamilton, G.A.; Martin, V.K.; Cannon, P.M. New world clade b arenaviruses can use transferrin receptor 1 (tfr1)-dependent and -independent entry pathways, and glycoproteins from human pathogenic strains are associated with the use of tfr1. J. Virol. 2008, 82, 938–948.
- Spiropoulou, C.F.; Kunz, S.; Rollin, P.E.; Campbell, K.P.; Oldstone, M.B. New world arenavirus clade c, but not clade a and b viruses, utilizes alpha-dystroglycan as its major receptor. J. Virol. 2002, 76, 5140–5146.
- Cao, W.; Henry, M.D.; Borrow, P.; Yamada, H.; Elder, J.H.; Ravkov, E.V.; Nichol, S.T.; Compans, R.W.; Campbell, K.P.; Oldstone, M.B. Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and lassa fever virus. Science 1998, 282, 2079–2081.
- Albarino, C.G.; Bergeron, E.; Erickson, B.R.; Khristova, M.L.; Rollin, P.E.; Nichol, S.T. Efficient reverse genetics generation of infectious junin viruses differing in glycoprotein processing. J. Virol. 2009, 83, 5606–5614.
- Hass, M.; Golnitz, U.; Muller, S.; Becker-Ziaja, B.; Gunther, S. Replicon system for lassa virus. J. Virol. 2004, 78, 13793–13803, doi:10.1128/JVI.78.24.13793-13803.2004.
- Lopez, N.; Jacamo, R.; Franze-Fernandez, M.T. Transcription and rna replication of tacaribe virus genome and antigenome analogs require n and l proteins: Z protein is an inhibitor of these processes. J. Virol. 2001, 75, 12241–12251.
- Young, P.R.; Howard, C.R. Fine structure analysis of pichinde virus nucleocapsids. J. Gen. Virol. 1983, 64 (Pt 4), 833–842.
- Lee, K.J.; Novella, I.S.; Teng, M.N.; Oldstone, M.B.; de La Torre, J.C. Np and l proteins of lymphocytic choriomeningitis virus (lcmv) are sufficient for efficient transcription and replication of lcmv genomic rna analogs. J. Virol. 2000, 74, 3470–3477, doi:10.1128/JVI.74.8.3470-3477.2000.
- Qi, X.; Lan, S.; Wang, W.; Schelde, L.M.; Dong, H.; Wallat, G.D.; Ly, H.; Liang, Y.; Dong, C. Cap binding and immune evasion revealed by lassa nucleoprotein structure. Nature 2010, 468, 779–783, doi:10.1038/nature09605.
- Martinez-Sobrido, L.; Giannakas, P.; Cubitt, B.; Garcia-Sastre, A.; de la Torre, J.C. Differential inhibition of type i interferon induction by arenavirus nucleoproteins. J. Virol. 2007, 81, 12696–12703.
- Agnihothram, S.S.; York, J.; Nunberg, J.H. Role of the stable signal peptide and cytoplasmic domain of g2 in regulating intracellular transport of the junin virus envelope glycoprotein complex. J. Virol. 2006, 80, 5189–5198, doi:10.1128/JVI.00208-06.
- Eichler, R.; Lenz, O.; Strecker, T.; Eickmann, M.; Klenk, H.D.; Garten, W. Identification of lassa virus glycoprotein signal peptide as a trans-acting maturation factor. EMBO Rep. 2003, 4, 1084–1088.
- Eichler, R.; Lenz, O.; Strecker, T.; Garten, W. Signal peptide of lassa virus glycoprotein gp-c exhibits an unusual length. FEBS Lett. 2003, 538, 203–206.
- Beyer, W.R.; Popplau, D.; Garten, W.; von Laer, D.; Lenz, O. Endoproteolytic processing of the lymphocytic choriomeningitis virus glycoprotein by the subtilase ski-1/s1p. J. Virol. 2003, 77, 2866–2872.
- Kunz, S.; Edelmann, K.H.; de la Torre, J.C.; Gorney, R.; Oldstone, M.B. Mechanisms for lymphocytic choriomeningitis virus glycoprotein cleavage, transport, and incorporation into virions. Virology 2003, 314, 168–178.
- Lenz, O.; ter Meulen, J.; Klenk, H.D.; Seidah, N.G.; Garten, W. The lassa virus glycoprotein precursor gp-c is proteolytically processed by subtilase ski-1/s1p. Proc. Natl. Acad. Sci. U.S.A 2001, 98, 12701–12705.
- York, J.; Romanowski, V.; Lu, M.; Nunberg, J.H. The signal peptide of the junin arenavirus envelope glycoprotein is myristoylated and forms an essential subunit of the mature g1-g2 complex. J. Virol. 2004, 78, 10783–10792.
- Jacamo, R.; Lopez, N.; Wilda, M.; Franze-Fernandez, M.T. Tacaribe virus z protein interacts with the l polymerase protein to inhibit viral rna synthesis. J. Virol. 2003, 77, 10383–10393.
- Wilda, M.; Lopez, N.; Casabona, J.C.; Franze-Fernandez, M.T. Mapping of the tacaribe arenavirus z-protein binding sites on the l protein identified both amino acids within the putative polymerase domain and a region at the n terminus of l that are critically involved in binding. J. Virol. 2008, 82, 11454–11460.
- Loureiro, M.E.; Wilda, M.; Levingston Macleod, J.M.; D'Antuono, A.; Foscaldi, S.; Marino Buslje, C.; Lopez, N. Molecular determinants of arenavirus z protein homo-oligomerization and l polymerase binding. J. Virol. 2011, 85, 12304–12314.
- Cornu, T.I.; de la Torre, J.C. Ring finger z protein of lymphocytic choriomeningitis virus (lcmv) inhibits transcription and rna replication of an lcmv s-segment minigenome. J. Virol. 2001, 75, 9415–9426.
- Borden, K.L.; Campbell Dwyer, E.J.; Salvato, M.S. An arenavirus ring (zinc-binding) protein binds the oncoprotein promyelocyte leukemia protein (pml) and relocates pml nuclear bodies to the cytoplasm. J. Virol. 1998, 72, 758–766.
- Kentsis, A.; Dwyer, E.C.; Perez, J.M.; Sharma, M.; Chen, A.; Pan, Z.Q.; Borden, K.L. The ring domains of the promyelocytic leukemia protein pml and the arenaviral protein z repress translation by directly inhibiting translation initiation factor eif4e. J. Mol. Biol. 2001, 312, 609–623.
- Borden, K.L.; Campbelldwyer, E.J.; Carlile, G.W.; Djavani, M.; Salvato, M.S. Two ring finger proteins, the oncoprotein pml and the arenavirus z protein, colocalize with the nuclear fraction of the ribosomal p proteins. J. Virol. 1998, 72, 3819–3826.
- Campbell Dwyer, E.J.; Lai, H.; MacDonald, R.C.; Salvato, M.S.; Borden, K.L. The lymphocytic choriomeningitis virus ring protein z associates with eukaryotic initiation factor 4e and selectively represses translation in a ring-dependent manner. J. Virol. 2000, 74, 3293–3300.
- Fan, L.; Briese, T.; Lipkin, W.I. Z proteins of new world arenaviruses bind rig-i and interfere with type i interferon induction. J. Virol. 2010, 84, 1785–1791.
- Casabona, J.C.; Levingston Macleod, J.M.; Loureiro, M.E.; Gomez, G.A.; Lopez, N. The ring domain and the l79 residue of z protein are involved in both the rescue of nucleocapsids and the incorporation of glycoproteins into infectious chimeric arenavirus-like particles. J. Virol. 2009, 83, 7029–7039.
- Eichler, R.; Strecker, T.; Kolesnikova, L.; ter Meulen, J.; Weissenhorn, W.; Becker, S.; Klenk, H.D.; Garten, W.; Lenz, O. Characterization of the lassa virus matrix protein z: Electron microscopic study of virus-like particles and interaction with the nucleoprotein (np). Virus Res. 2004, 100, 249–255.
- Perez, M.; Craven, R.C.; de la Torre, J.C. The small ring finger protein z drives arenavirus budding: Implications for antiviral strategies. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 12978–12983.
- Strecker, T.; Eichler, R.; Meulen, J.; Weissenhorn, W.; Dieter Klenk, H.; Garten, W.; Lenz, O. Lassa virus z protein is a matrix protein and sufficient for the release of virus-like particles. J. Virol. 2003, 77, 10700–10705.
- Urata, S.; Yasuda, J.; de la Torre, J.C. The z protein of the new world arenavirus tacaribe virus has bona fide budding activity that does not depend on known late domain motifs. J. Virol. 2009, 83, 12651–12655.
- Hoenen, T.; Kolesnikova, L.; Becker, S. Recent advances in filovirus- and arenavirus-like particles. Future Virology 2007, 2, 193–203.
- Chen, B.J.; Lamb, R.A. Mechanisms for enveloped virus budding: Can some viruses do without an escrt? Virology 2008, 372, 221–232, doi:10.1016/j.virol.2007.11.008.
- Bieniasz, P.D. Late budding domains and host proteins in enveloped virus release. Virology 2006, 344, 55–63, doi:10.1016/j.virol.2005.09.044.
- Hurley, J.H.; Hanson, P.I. Membrane budding and scission by the escrt machinery: It's all in the neck. Nat. Rev. Mol. Cell. Biol. 2010, 11, 556–566.
- Freed, E.O. Viral late domains. J. Virol. 2002, 76, 4679–4687.
- Schmitt, A.P.; Leser, G.P.; Morita, E.; Sundquist, W.I.; Lamb, R.A. Evidence for a new viral late-domain core sequence, fpiv, necessary for budding of a paramyxovirus. J. Virol. 2005, 79, 2988–2997.
- Shtanko, O.; Watanabe, S.; Jasenosky, L.D.; Watanabe, T.; Kawaoka, Y. Alix/aip1 is required for np incorporation into mopeia virus z-induced virus-like particles. J. Virol. 2011, 85, 3631–3641.
- Strack, B.; Calistri, A.; Craig, S.; Popova, E.; Gottlinger, H.G. Aip1/alix is a binding partner for hiv-1 p6 and eiav p9 functioning in virus budding. Cell 2003, 114, 689–699, doi:10.1016/S0092-8674(03)00653-6.
- Dilley, K.A.; Gregory, D.; Johnson, M.C.; Vogt, V.M. An lypsl late domain in the gag protein contributes to the efficient release and replication of rous sarcoma virus. J. Virol. 2010, 84, 6276–6287.
- Sakaguchi, T.; Kato, A.; Sugahara, F.; Shimazu, Y.; Inoue, M.; Kiyotani, K.; Nagai, Y.; Yoshida, T. Aip1/alix is a binding partner of sendai virus c protein and facilitates virus budding. J. Virol. 2005, 79, 8933–8941.
- Irie, T.; Shimazu, Y.; Yoshida, T.; Sakaguchi, T. The yldl sequence within sendai virus m protein is critical for budding of virus-like particles and interacts with alix/aip1 independently of c protein. J. Virol. 2007, 81, 2263–2273.
- Harty, R.N.; Paragas, J.; Sudol, M.; Palese, P. A proline-rich motif within the matrix protein of vesicular stomatitis virus and rabies virus interacts with ww domains of cellular proteins: Implications for viral budding. J. Virol. 1999, 73, 2921–2929.
- Timmins, J.; Schoehn, G.; Ricard-Blum, S.; Scianimanico, S.; Vernet, T.; Ruigrok, R.W.; Weissenhorn, W. Ebola virus matrix protein vp40 interaction with human cellular factors tsg101 and nedd4. J. Mol. Biol. 2003, 326, 493–502.
- Kikonyogo, A.; Bouamr, F.; Vana, M.L.; Xiang, Y.; Aiyar, A.; Carter, C.; Leis, J. Proteins related to the nedd4 family of ubiquitin protein ligases interact with the l domain of rous sarcoma virus and are required for gag budding from cells. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 11199–11204.
- Garrus, J.E.; von Schwedler, U.K.; Pornillos, O.W.; Morham, S.G.; Zavitz, K.H.; Wang, H.E.; Wettstein, D.A.; Stray, K.M.; Cote, M.; Rich, R.L.; et al. Tsg101 and the vacuolar protein sorting pathway are essential for hiv-1 budding. Cell 2001, 107, 55–65.
- Dolnik, O.; Kolesnikova, L.; Stevermann, L.; Becker, S. Tsg101 is recruited by a late domain of the nucleocapsid protein to support budding of marburg virus-like particles. J. Virol. 2010, 84, 7847–7856.
- Irie, T.; Licata, J.M.; McGettigan, J.P.; Schnell, M.J.; Harty, R.N. Budding of ppxy-containing rhabdoviruses is not dependent on host proteins tgs101 and vps4a. J. Virol. 2004, 78, 2657–2665.
- Urata, S.; Noda, T.; Kawaoka, Y.; Yokosawa, H.; Yasuda, J. Cellular factors required for lassa virus budding. J. Virol. 2006, 80, 4191–4195.
- Pornillos, O.; Alam, S.L.; Rich, R.L.; Myszka, D.G.; Davis, D.R.; Sundquist, W.I. Structure and functional interactions of the tsg101 uev domain. EMBO J. 2002, 21, 2397–2406.
- Harty, R.N.; Brown, M.E.; Wang, G.; Huibregtse, J.; Hayes, F.P. A ppxy motif within the vp40 protein of ebola virus interacts physically and functionally with a ubiquitin ligase: Implications for filovirus budding. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 13871–13876.
- Yasuda, J.; Hunter, E. A proline-rich motif (pppy) in the gag polyprotein of mason-pfizer monkey virus plays a maturation-independent role in virion release. J. Virol. 1998, 72, 4095–4103.
- Carpp, L.N.; Galler, R.; Bonaldo, M.C. Interaction between the yellow fever virus nonstructural protein ns3 and the host protein alix contributes to the release of infectious particles. Microbes Infect. 2010, 13, 85–95.
- Fisher, R.D.; Chung, H.Y.; Zhai, Q.; Robinson, H.; Sundquist, W.I.; Hill, C.P. Structural and biochemical studies of alix/aip1 and its role in retrovirus budding. Cell 2007, 128, 841–852.
- Perez, M.; Greenwald, D.L.; de la Torre, J.C. Myristoylation of the ring finger z protein is essential for arenavirus budding. J. Virol. 2004, 78, 11443–11448.
- Strecker, T.; Maisa, A.; Daffis, S.; Eichler, R.; Lenz, O.; Garten, W. The role of myristoylation in the membrane association of the lassa virus matrix protein z. Virol. J. 2006, 3, 93.
- Shtanko, O.; Imai, M.; Goto, H.; Lukashevich, I.S.; Neumann, G.; Watanabe, T.; Kawaoka, Y. A role for the c terminus of mopeia virus nucleoprotein in its incorporation into z protein-induced virus-like particles. J. Virol. 2010, 84, 5415–5422.
- Groseth, A.; Wolff, S.; Strecker, T.; Hoenen, T.; Becker, S. Efficient budding of the tacaribe virus matrix protein z requires the nucleoprotein. J. Virol. 2010, 84, 3603–3611.
- Schmitt, A.P.; Leser, G.P.; Waning, D.L.; Lamb, R.A. Requirements for budding of paramyxovirus simian virus 5 virus-like particles. J. Virol. 2002, 76, 3952–3964.
- Li, M.; Schmitt, P.T.; Li, Z.; McCrory, T.S.; He, B.; Schmitt, A.P. Mumps virus matrix, fusion, and nucleocapsid proteins cooperate for efficient production of virus-like particles. J. Virol. 2009, 83, 7261–7272, doi:10.1128/JVI.00421-09.
- Bello, N.F.; Dussupt, V.; Sette, P.; Rudd, V.; Nagashima, K.; Bibollet-Ruche, F.; Chen, C.; Montelaro, R.C.; Hahn, B.H.; Bouamr, F. Budding of retroviruses utilizing divergent l domains requires nucleocapsid. J. Virol. 2012, 86, 4182–4193.
- Licata, J.M.; Johnson, R.F.; Han, Z.; Harty, R.N. Contribution of ebola virus glycoprotein, nucleoprotein, and vp24 to budding of vp40 virus-like particles. J. Virol. 2004, 78, 7344–7351, doi:10.1128/JVI.78.14.7344-7351.2004.
- Dussupt, V.; Sette, P.; Bello, N.F.; Javid, M.P.; Nagashima, K.; Bouamr, F. Basic residues in the nucleocapsid domain of gag are critical for late events of hiv-1 budding. J. Virol. 2011, 85, 2304–2315.
- Radoshitzky, S.R.; Dong, L.; Chi, X.; Clester, J.C.; Retterer, C.; Spurgers, K.; Kuhn, J.H.; Sandwick, S.; Ruthel, G.; Kota, K.; et al. Infectious lassa virus, but not filoviruses, is restricted by bst-2/tetherin. J. Virol. , 2010 84, 10569–10580.
- Sakuma, T.; Noda, T.; Urata, S.; Kawaoka, Y.; Yasuda, J. Inhibition of lassa and marburg virus production by tetherin. J. Virol. 2009, 83, 2382–2385, doi:10.1128/JVI.01607-08.
- Neil, S.J.; Zang, T.; Bieniasz, P.D. Tetherin inhibits retrovirus release and is antagonized by hiv-1 vpu. Nature 2008, 451, 425–430.
- Van Damme, N.; Goff, D.; Katsura, C.; Jorgenson, R.L.; Mitchell, R.; Johnson, M.C.; Stephens, E.B.; Guatelli, J. The interferon-induced protein bst-2 restricts hiv-1 release and is downregulated from the cell surface by the viral vpu protein. Cell Host Microbe. 2008, 3, 245–252, doi:10.1016/j.chom.2008.03.001.
- Franke, T.F. Intracellular signaling by akt: Bound to be specific. Sci Signal 2008, 1, pe29, doi:10.1126/scisignal.124pe29.
- Saeed, M.F.; Kolokoltsov, A.A.; Freiberg, A.N.; Holbrook, M.R.; Davey, R.A. Phosphoinositide-3 kinase-akt pathway controls cellular entry of ebola virus. PLoS Pathog. 2008, 4, e1000141, doi:10.1371/journal.ppat.1000141.
- Sun, M.; Fuentes, S.M.; Timani, K.; Sun, D.; Murphy, C.; Lin, Y.; August, A.; Teng, M.N.; He, B. Akt plays a critical role in replication of nonsegmented negative-stranded rna viruses. J. Virol. 2008, 82, 105–114, doi:10.1128/JVI.01520-07.
- Linero, F.N.; Scolaro, L.A. Participation of the phosphatidylinositol 3-kinase/akt pathway in junin virus replication in vitro. Virus Res. 2009, 145, 166–170, doi:10.1016/j.virusres.2009.07.004.
- Urata, S.; Ngo, N.; de la Torre, J.C. The pi3k/akt pathway contributes to arenavirus budding. J. Virol. 2012, 86, 4578–4585, doi:10.1128/JVI.06604-11.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).