Virology 271, 1–8 (2000) doi:10.1006/viro.2000.0216, available online at http://www.idealibrary.com on

MINIREVIEW

Foamy : Between and Pararetroviruses

Charles-Henri Lecellier and Ali Saı¨b 1

CNRS UPR9051, Universite´Paris 7, Hoˆpital Saint-Louis, 75475 Paris Cedex 10, France Received November 18, 1999; returned to author for revision December 14, 1999; accepted January 21, 2000

Foamy viruses, also called spumaviruses or spuma- sory from the 3Ј end of the viral genome (Reth- retroviruses, are retroviruses described for the first time wilm et al., 1987). Construction of infectious clones of in 1954 in cultures derived from monkey kidneys HFV and cloning of viral genes out of the viral context (Enders et al., 1954). They are so named because of the allowed the study of the viral replication cycle and the specific cytopathic foam effect they induce in culture, implication of each gene product. One remarkable find- with the concomitant appearance of syncytia, facilitating ing is the striking similarity between FVs and the hepa- their isolation. In culture, FVs are highly lytic and present titis B (HBV, the prototype of hepadnaviruses) con- a large cellular tropism that reflects the ubiquity of the cerning the strategy used to replicate their genome (See- viral receptor (Hill et al., 1999). These viruses were ger et al., 1996). mainly isolated from primate species and also from non- The Third International Conference on Foamy Viruses, primates, such as cats ( [FeFV]) or held in Paris in June 1999, has brought new insights into cattle (bovine foamy virus [BFV]) and more recently from our understanding of these particular viruses, confirming horses (Tobaly-Tapiero et al., 1999) (Table 1). Absent in their existence somewhere at the “crossroad” between humans, these viruses are innocuous in their natural retroviruses and pararetroviruses. hosts and remain apathogenic in accidentally infected Molecular cloning of foamy viruses indicated that they humans. have the longest genomes among the retroviral family. By electron microscopy, foamy viruses appear as The genome of FVs is a linear RNA ranging from 11.956 spheres of 100–140 nm diameter, coated with 5- to 15-nm to 13.246 kb in length, which is reverse-transcribed into spikes, distinguishing them from other retroviruses. Viri- a double-stranded DNA during the viral cycle. Similarly ons are completely assembled in the of the as for and two fish retroviruses, the Walley host cell and have a strong tendency to remain cell- dermal sarcoma virus (WDSV) and the Walleye epidermal associated. In contrast to other exogenous retroviruses, hyperplasia virus (WEHV), the linear and unintegrated no more maturation occurs after their release and vi- viral form of FVs possesses a second and internal poly- ruses bud essentially from the purine tract at the middle of the viral genome (3Ј of the (ER). In 1971, the FV prototype HFV (human foamy virus) pol gene), used as a second site of initiation of the was isolated and cloned from lymphoblastoid cells of a positive strand during reverse transcription (Kupiec et al., patient with a (Achong et al., 1988; LaPierre et al., 1999) (Fig. 1). This double initiation 1971a,b). However, recent studies revealed that FVs are results in a gapped unintegrated intermediate viral DNA. not prevalent in humans (Heneine et al., 1998) and that For the analysis of viral replication and characteristics of nucleotide sequence of HFV is identical to simian iso- viral proteins, we focused on HFV, the most studied FV. lates from chimpanzees (Herchenro¨der et al., 1994). The long terminal repeat (LTR) of the linear viral DNA Therefore, a new nomenclature is needed to indicate that has a typical U3-R-U5 structure. The length of these LTRs HFV is a simian FV isolated from a human cell line. is larger than other exogenous retroviruses, except those Sequence analysis of HFV showed that FVs are com- of MMTV or HIV-1. This characteristic could be explained plex retroviruses because, in addition to the canonical in part by the open reading frame found in the U3 region gag, pol, and env retroviral genes, they encode acces- of these retroviruses: sag for MMTV, nef for HIV-1, and bel2/bel3 for HFV. The size of the RNA leader sequence encoded by the LTR, present in all viral mRNAs is, so far, 1 To whom correspondence and reprint requests should be ad- the shortest discovered among retroviruses (51 bp) (Mu- dressed. Fax: 33-1-42-06-4857. E-mail: [email protected]. ranyi et al., 1991). In the U3 domain, few DNA recognition

0042-6822/00 $35.00 1 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved. 2 MINIREVIEW

TABLE 1 of NC to the viral RNA, a function performed by GRI in Foamy Virus Isolated from Different Animal Species FVs, which interacts nonspecifically with nucleic acids; while GRII, which contains a nuclear localization se- Species Reference quence, targets the Gag to the nucleus (Schliephake et al., 1994). Note that the core protein of Rhesus monkey Enders and Peebles, 1954 the harbors similar glycine-arginine-rich Macaque SFV1 Rustigian et al., 1955 Macaque SFV2 Johnston, 1961 regions that interact with the viral RNA at the early stage Cercopithecus SFV3 Stiles et al., 1964 of infection and with the viral DNA during virion assem- Bovine Malmquist et al., 1969 bly. Indeed HBVs, together with two plant viruses (Cauli- Feline Fabricant et al., 1969 movirus and Badnavirus), are complex DNA viruses that Cat Riggs et al., 1969 are also called pararetroviruses since they encode for a Human HFV Achong et al., 1971 Squirrel monkey SFV4 Johnston, 1971 used to complete their replication Prosimian SFV5 Johnston, 1971 cycle (Fig. 2). Chimpanzee SFV6 Hooks et al., 1972 The 127-kDa Pol precursor is processed into the viral Chimpanzee SFV7 Hooks et al., 1972 protease, the reverse transcriptase-RNase H, and the Spider monkey SFV8 Hooks et al., 1973 , respectively, of 10, 80, and 40 kDa molecular Hamster Fabisch et al., 1973 Cebus monkey Hooks et al., 1975 weight. Papio hamadryas baboon Rabin et al., 1976 The env gene encodes for a 130-kDa glycoprotein Red uakari monkey Barahona et al., 1976 precursor, which is cleaved into the surface (SU, gp70– Human Cameron et al., 1978 80) and the transmembrane (TM, gp48) proteins by a Papio cynocephalus baboon SFV10 Rhodes-Feuillette et al., 1979 subtilisin-like protease (Giron et al., 1993). Unlike other Human Werner and Gelderblom, 1979 Marmoset Marczynska et al., 1981 exogenous retroviruses, Env is indispensable for viral Californian sea lion Kennedy-Stoskopf et al., 1986 particle formation (Baldwin et al., 1998). One character- Sheep Flanagan et al., 1992 istic of FVs also shared by HBV is their budding from the Orangutan SFV11 McClure et al., 1994 ER. For FVs, this is the result of an ER retrieval motif, Gorilla SFVGg Bieniasz et al., 1994 commonly found in type I transmembrane proteins and Chimpanzee SFVcpz Herchenro¨der et al., 1994 Ϫ Ϫ Ϫ Horse EFV Tobaly-Tapiero et al., 1999 consisting of two lysin at positions 3 and 4or 5 from the C-terminal end of TM (Goepfert et al., 1995). Mutations of this motif, although enhancing budding from elements for cellular transcription factors have been de- the plasma membrane, do not affect infectivity nor a scribed: three consensus AP1 sites, which slightly con- possible Gag-Env interaction, at least in vitro (Goepfert et tribute to the optimal activity of the LTR; and two ets sites, al., 1999). However, it can be postulated that in vivo, which have not been studied in great detail (Schmidt et budding from internal cellular membranes might be use- al., 1997). Negative regulatory elements have been de- ful to escape the host immune system. scribed within the R-U5 domain but also in the U3 region In agreement with what we know from other retrovi- (Mergia et al., 1992; Erlwein et al., 1993) (Fig. 1). ruses, pol is the most conserved gene among FVs struc- For retroviruses, the Gag precursor is encoded by the tural genes, while surprisingly, gag diverges more than full-length mRNA and is cleaved by the viral protease the env gene, probably because of the dissociation of (encoded by Pol) into three mature products: the matrix Gag and Pol synthesis in FVs (Wang et al., 1999, see (MA), the (CA), and the nucleocapsid (NC). In FVs, below). Gag maturation does not follow the same processing Foamy viruses belong to the family of complex retro- and the 72-kDa Gag precursor is principally cleaved near viruses as in addition to the structural gag, pol, and env the C-terminus into 4- and 68-kDa mature products. genes, they harbor accessory genes in the 3Ј end of their Thus, although other minor proteolytic cleavages occur genome (Flu¨gel et al., 1987). These genes have been within the 68-kDa product, the classical tripartite retrovi- originally called bel (for between env and LTR) because ral division of Gag does not exist in FVs and two high of their specific location along the genome (Fig. 3). In- molecular weight precursors of 72 and 68 kDa are de- deed, in contrast to the other complex retroviruses in tected mainly in infected cells (Pfrepper et al., 1999). which the exons encoding regulatory genes flank the env Moreover, in contrast to other retroviruses, the C-termi- gene, in FVs these open reading frames (ORFs) are nal domain of HFV Gag (which corresponds to the retro- located within coding exons inserted between the env viral NC gene product for other retroviruses) contains gene and the 3Ј LTR. Note that two accessory genes three glycine/arginine-rich basic sequences (the GR (orfA and orfB) of WDSV and WEHV are also located boxes) instead of the canonical cysteine-histidine repeat downstream of the env gene (LaPierre et al., 1999). For motif. Note that WEHV and WDSV also contain a GR motif FVs, this particular location must be linked to the pres- in addition to a Cys-His box in the C-terminal of NC ence of an internal promotor directing the expression of (LaPierre et al., 1999). This latter motif allows the fixation the regulatory genes (Fig. 1). It will be interesting to MINIREVIEW 3

FIG. 1. Schematic representation of the HFV DNA genome. AATAAA, polyadenylation signal; BRE, Bel1/Tas responsive element; LTR, long terminal repeat; IP, internal promotor; PBS, primer binding site complementary to the 3Ј end of tRNAlys1,2; PPT, polypurine tract; SI, SII, and SII: RNA dimerization signals; SD, splice donor site; TATAA, TATA box; ␺, encapsidation signal. check for the presence of such a promotor in WDSV and Bet. However, only Bet has been detected in infected WEHV. cells. This protein derives from a multiply spliced mRNA The first regulatory protein characterized was the viral fusing the first 88 N-terminal amino acids of Tas to the transactivator Tas (transactivator of spumavirus, initially entire Bel2 open reading frame. This protein, which is not termed Bel1). This 36-kDa nuclear phosphoprotein, es- detected in viral particles, is highly abundant in infected sential for viral gene expression, has been shown to cells and although predominantly located in the cyto- transactivate the LTR by direct binding to the viral DNA plasm, Bet is also found in the nucleus of infected cells. (He et al., 1996). Although no similarity in protein se- Like Tat from HIV, Bet is secreted by infected cells and quence between Tas and other viral transactivators has internalized by surrounding naive cells, suggesting that been demonstrated, important functional domains have this protein could act from a distance in vivo (Giron et al., been defined (Fig. 3). The activating domain has been 1993). Mutational analysis of the 3Ј end of HFV revealed mapped to the carboxyl-terminal end of the protein and that only Tas is essential for viral replication, at least in harbors a motif highly conserved among foamy viruses vitro, demonstrating the absence of a posttranscriptional transactivators (aa 273–287), representing the minimal regulator (Baunach et al., 1993; Yu et al., 1993; Lee et al., activation domain (He et al., 1993). Study of fusion pro- 1994). Although not essential for viral replication, Bet teins between Tas and VP16 has delimited a putative might be an important factor in the establishment of DNA binding domain located in the middle part of the persistence in vivo as recently described in cell cultures protein, near a nuclear localization signal (NLS) (Lee et (Saı¨b et al., 1995; Bock et al., 1998). However, study of al., 1994; Chang et al., 1995) (Fig. 3). transmitted FVs in accidentally infected humans re- Computer analyses have described the existence of vealed that most of these viruses harbor deleterious other putative accessory ORFs for HFV: Bel2, Bel3, and mutations in the Bel2 ORF, suggesting that persistence of 4 MINIREVIEW

FIG. 2. Replication cycle of hepadnaviruses.

FVs in these particular cases might involve other mech- temporal regulation of viral gene expression is a strategy anisms in relation with the host immune system (Calla- in current use by complex DNA viruses but absent in han et al., 1999). retroviruses. Finally, an Env-Bet fusion protein has been recently Genomic structure of FVs, which obviously resembles described (Giron et al., 1998; Lindemann et al., 1998). that of other retroviruses, suggests that their replication This glycoprotein is secreted by infected cells, since it might follow similar pathways (Fig. 4). In that sense, a derives from a multiply spliced mRNA fusing the Env tRNAlys1,2 complementary to the primer binding sequence glycoprotein to the Bet ORF by deleting the membrane- (PBS) is used as a template for initiation of reverse spanning domain of Env (Fig. 3). transcription, two polypurine tracts are used as primers In complex retroviruses, multiply spliced viral , for positive-strand DNA synthesis, and specific cis-acting corresponding to regulatory proteins, are abundantly sequences in the 5Ј end of the genome as well as in pol produced during the early phase of infection. The late are involved in viral genome packaging (Erlwein et al., phase is characterized by a shift in RNA expression 1998) (Fig. 1). Although most of the viral DNA genome is toward those of structural genes (genomic and singly not integrated during the acute phase of infection, inte- spliced Env RNAs). This shift is induced by the Rev/Rex- gration does occur; the study of integrated forms in like proteins in other complex retroviruses (Parslow, chronically infected cells suggested that FVs integrate 1993). Despite the presence of early and late phases in into the cellular genome via a classical mechanism foamy virus infection, thus far no structural or functional (Neves et al., 1998; Enssle et al., 1999). Note that, in Rev/Rex homolog has been described. To circumvent contrast to hepadnaviruses, integration of the provirus this lack, foamy viruses have developed an original reg- and therefore integrity of the integrase domain is needed ulation of viral gene expression. Indeed, S1 nuclease to achieve a productive infection (Enssle et al., 1999). protection assay and primer extension analysis demon- Despite these characteristics encountered in all retro- strated the existence of an internal ϩ1 initiation site of viruses, FVs present some peculiarities that distinguish transcription located within the 3Ј end of the env gene, them from the rest of the retroviral family. Indeed, FVs 180 bp upstream of the tas gene (Lo¨chelt et al., 1993) were recently shown to produce their Pol protein from a (Fig. 3). This Tas-dependent internal promotor (IP) has a specific mRNA, in contrast to other retroviruses which high basal activity, in contrast to the LTR which remains have evolved mechanisms such as frameshift or leaky silent in the absence of the viral transactivator. Transcrip- stop to produce Pol as a Gag-Pol polyprotein from the tion from this promotor leads to Tas expression early in full-length mRNA (Yu et al., 1996). This latter strategy the viral cycle, which in turn enhances its own produc- simplifies incorporation of Pol into the nascent particle tion from the IP and expression of structural proteins and limits reverse transcription of cellular mRNAs, while from the LTR (Lo¨chelt et al., 1994, 1995). This type of favoring that of viral RNAs into the viral particle. Thus, for MINIREVIEW 5

FIG. 3. Schematic representation of the 3Ј end of the HFV DNA genome. DB, DNA binding domain; FP, fusion peptide; IP, internal promotor; MD, multimerization domain; MSD, membrane spanning domain; SU, surface domain of Env; TA, transactivation domain; TM, transmembrane domain of Env; NLS, nuclear localization signal. foamy viruses, incorporation of Pol into the virion might genetically stable in vivo despite a high replication rate occur either via protein–protein interactions with Gag in vivo (Schweizer et al., 1999). One possible answer (note that the mechanism of Gag incorporation is not could lie in the existence of two molecular forms of FVs known, since this protein is not myristylated), or by in- provirus. Indeed, in the case of HFV, the shorter form teracting with the viral genome as is the case for the P (⌬HFV, also named HFV⌬Tas) contains a 301-bp deletion protein of HBV, which is also produced from a specific in the tas gene, generated by an alternative splicing mRNA (Table 2). event of the pregenomic RNA, leading to the formation of Moreover, in the same study, the authors demon- an intronless bet gene (Saı¨b et al., 1993). ⌬HFV is there- strated that infectious full-length viral DNA molecules are fore defective in the absence of exogenous Tas but packaged into extracellular virions, suggesting that the expresses high rates of Bet when transactivated. The viral genome is likely to be DNA rather than RNA. This existence of this deletion seems to be a general feature hypothesis is strengthened by the inefficiency of AZT of foamy viruses as it has been described in all other (3Ј-azido-3Ј-deoxythymidine) treatment in the early spumaviruses described to date. ⌬HFV is distinctly more phase of infection (Yu et al., 1999). abundant in persistent infections in vitro as well as in One of the main features of foamy viruses is their vivo and cells harboring ⌬HFV exhibit a distinct resis- ability to persist in their hosts, although highly lytic in tance to HFV-induced lysis, evoking the situation en- vitro. The mechanism of persistence is not elucidated yet countered in other viral systems in which natural defec- but, unlike lentiviruses, genetic variability is likely not tive interfering mutants act as negative feedback toward involved in this equilibrium because these viruses are their cognate parental viruses. Recently, cell lines ex- 6 MINIREVIEW

FIG. 4. Replication cycle of foamy viruses compared to that of retroviruses. Mt, microtubule. pressing only the viral Bet protein were shown to be studies demonstrate the absence of FVs in humans and resistant to HFV-induced cell lysis, suggesting a direct accidentally infected laboratory workers or African hunt- implication of this protein in viral persistence (Bock et al., ers bitten by monkeys constitute the only rare cases of 1998). FV zoonotic infections (Heneine et al., 1998). In these It is assumed today that FVs are apathogenic viruses persistent infections, no horizontal transmission has in their natural hosts. After numerous attempts to asso- been detected, suggesting that humans may represent ciate FVs to a specific human disease in the past, recent dead-end hosts (Callahan et al., 1999). This peculiarity, MINIREVIEW 7

TABLE 2 W., Folks, T. M., and Sandstrom, P. A. (1999). Persistent zoonotic infection of a human with in the absence of an Summary of Principal Characteristics of Foamy Viruses Compared intact orf-2 accessory gene. J. Virol. 73, 9619–9624. with Those of Hepadnaviruses and Exogenous Retroviruses Cameron, K. R., Birchall, S. M., and Moses, M. A. (1978). Isolation of foamy virus from patient with dialysis encephalopathy [letter]. Lancet Foamy Exogenous 2, 796. Properties Hepadnavirus virus Chang, J., Lee, K. J., Jang, K. L., Lee, E. K., Baek, G. H., and Sung, Y. C. (1995). Human foamy virus Bel1 transactivator contains a bipartite Genome DNA DNA/RNA? RNA nuclear localization determinant which is sensitive to protein context Reverse transcription late late early and triple multimerization domains. J. Virol. 69, 801–808. Primer for minus- P protein tRNA tRNA Enders, J., and Peebles, T. (1954). Propagation in tissue culture of strand synthesis cutopathogenic agents from patients with measles. Proc. Soc. Exp. mRNA pool yes yes no Biol. Med. 86, 277–287. Integration rare yes yes Enssle, J., Moebes, A., Heinkelein, M., Panhuysen, M., Mauer, B., Budding ER ER plasma Schweizer, M., Neumann-Haefelin, D., and Rethwilm, A. (1999). An membrane active foamy virus integrase is required for virus replication. J. Gen. Virol. 80, 1445–1452. Erlwein, O., Bieniasz, P. D., and McClure, M. O. (1998). Sequences in pol are required for transfer of human foamy virus-based vectors. J. Virol. together with their large cellular tropism and their pack- 72, 5510–5516. aging potential, makes FVs interesting tools for gene Erlwein, O., and Rethwilm, A. (1993). BEL-1 transactivator responsive therapy. sequences in the long terminal repeat of human foamy virus. Virology Although presenting striking similarities to pararetro- 196, 256–268. viruses, in their genomic structure, the presence of inte- Fabisch, P. H., Takemoto, K. K., and Hruska, J. F. (1973). Characterisation of a hamster “foamy” virus. Ann. Met. Am. Soc. Microbiol. 365, 255. grase and protease genes indicate foamy viruses clearly Fabricant, C. G., Rich, L. J., and Gillepsie, J. H. (1969). Felinevirus. IX. belong to the retroviral family. Recent advances in our Isolation of a virus similar to a myxovirus from cats in which uroli- understanding of FV in vitro may answer certain thiasis was experimentally induced. Cornell Vet. 59, 667–672. questions but they raise many more. For instance, how Flanagan, M. (1992). Isolation of a spumavirus from a sheep. Aust. Vet. does this virus enter its target cells? One intriguing issue J. 69, 112–113. is how a virus that is so highly lytic in vitro can be so well Flu¨gel, R. M., Rethwilm, A., Maurer, B., and Darai, G. (1987). Nucleotide sequence analysis of the env gene and its flanking regions of the tolerated in vivo. Study of relationships between the virus human spumaretrovirus reveals two novel genes [published erratum and the host immune system will certainly shed a new appears in EMBO J. 1990, Nov;9(11):3806]. EMBO J. 6, 2077–2084. light on this point. In that sense, FV infection was re- Giron, M. L., de The´, H., and Saı¨b, A. (1998). An evolutionarily conserved cently shown to be lethal in nude mice (Horst et al., splice generates a secreted env-Bet fusion protein during human 1999). foamy virus infection. J. Virol. 72, 4906–4910. Giron, M. L., Rozain, F., Debons-Guillemin, M. C., Canivet, M., Pe´rie`s, J., and Emanoil-Ravier, R. (1993). Human foamy virus polypeptides: ACKNOWLEDGMENTS Identification of env and bel gene products. J. Virol. 67, 3596–3600. The authors thank M. P. Grange for her contribution and C. Pique for Goepfert, P. A., Shaw, K., Wang, G., Bansal, A., Edwards, B. 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