Virology 271, 1–8 (2000) doi:10.1006/viro.2000.0216, available online at http://www.idealibrary.com on MINIREVIEW Foamy Viruses: Between Retroviruses 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 proteins 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 cell 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 virus (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 (feline foamy virus [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 cytoplasm of the as for lentiviruses 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 endoplasmic reticulum 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 nasopharyngeal carcinoma (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 protein to the nucleus (Schliephake et al., 1994). Note that the core protein of Rhesus monkey Enders and Peebles, 1954 the hepatitis B virus 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 reverse transcriptase 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 integrase, 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 capsid (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.