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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.
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