historical perspective of foamy virus epidemiology and ... · foamy viruses (fv), or spumaviruses,...

CLINICAL MICROBIOLOGY REVIEWS,0893-8512/01/$04.0010 DOI: 10.1128/CMR.14.1.165–176.2001

Jan. 2001, p. 165–176 Vol 14, No. 1

Copyright © 2001, American Society for Microbiology. All Rights Reserved.

Historical Perspective of Foamy Virus Epidemiology and InfectionCHRISTOPHER D. MEIERING1,2 AND MAXINE L. LINIAL1,2*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,1 andDepartment of Microbiology, University of Washington, Seattle, Washington 981952

REPLICATION ...........................................................................................................................................................165Viral Genome...........................................................................................................................................................165Viral Life Cycle .......................................................................................................................................................166In Vitro Tropism.....................................................................................................................................................166

NATURAL HISTORY.................................................................................................................................................166Origin of “Human” FV ..........................................................................................................................................167FV Prevalence..........................................................................................................................................................167FV Transmission.....................................................................................................................................................167

ANIMAL MODELS OF FV INFECTION ...............................................................................................................168Rabbits .....................................................................................................................................................................168Mice ..........................................................................................................................................................................169Transgenic Mice......................................................................................................................................................169

FV INFECTION AND HUMAN DISEASE .............................................................................................................170Thyroiditis de Quervain.........................................................................................................................................171Graves’ Disease .......................................................................................................................................................171Multiple Sclerosis ...................................................................................................................................................171Myasthenia Gravis..................................................................................................................................................171Other Diseases ........................................................................................................................................................171

FV PREVALENCE IN HUMANS .............................................................................................................................172Early Serological Studies.......................................................................................................................................172Epidemiological Studies.........................................................................................................................................172Zoonotic Infections .................................................................................................................................................172Baboon Liver Transplants .....................................................................................................................................173

FV PERSISTENCE.....................................................................................................................................................173Isolation from Infected Individuals......................................................................................................................173Sites of Viral Persistence .......................................................................................................................................173

VECTORS ....................................................................................................................................................................174CONCLUSIONS .........................................................................................................................................................174REFERENCES ............................................................................................................................................................174

INTRODUCTION

Foamy viruses (FV), or Spumaviruses, comprise one of theseven genera of Retroviridae. They have a distinct morphologyand bud primarily from the endoplasmic reticulum rather thanthe plasma membrane (Fig. 1). The particles are characterizedby an immature-looking core with an electron-lucent centerand very distinct glycoprotein spikes on the surface. Since theirdiscovery in a human-derived cell culture in 1971, FV havebeen implicated in a variety of human pathologies. In thisreview we examine FV epidemiology and the putative relation-ship between FV infection and human disease.

REPLICATION

Viral Genome

FV are considered complex retroviruses because they en-code viral proteins which are not incorporated into viral par-

ticles. The prototype FV genome, SFVcpz(hu), which has beenmost commonly designated human FV in the literature, isdepicted in Fig. 2. Throughout this review, the nomenclaturepresented in Table 1 is used. Such nomenclature has beenproposed because it clearly indicates the origin of each FVisolate. The FV genome encodes the canonical retroviral gag,pol, and env genes, as well as at least two additional genestermed tas (bel-1) and bet. Although a number of putativefunctions have been proposed for the SFVcpz(hu) bet gene, itsrole in vivo is still unknown; it is dispensable for replication intissue culture. In contrast, the tas gene, for transactivator ofspumavirus, is required for viral replication (68). The tas geneencodes a protein which functions to transactivate the longterminal repeat (LTR) promoter, which in the absence of Tasis transcriptionally silent (77, 87). In addition to the LTR, FVcontain a second promoter, termed the internal promoter (IP)because it is located within the env gene (23, 65, 67, 75). The IPdrives expression of the tas and bet genes but, unlike the LTR,has significant basal transcription activity (66). In a mannersimilar to the LTR, the IP is also transactivated by Tas protein.Studies in infected fibroblasts indicate that early in infection,the IP drives expression of tas and bet mRNAs (66). Oncethese mRNAs are translated and Tas protein is synthesized,

* Corresponding author. Mailing address: Division of Basic Sci-ences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave.N., Seattle, WA 98109. Phone: (206) 667-4442. Fax: (206) 667-5939.E-mail: [email protected].

165

on October 18, 2020 by guest

http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

transcription begins from the LTR, leading to the accumula-tion of gag, pol, and env mRNAs and ultimately to new viralparticles.

FV structural genes have features distinct to this genus. TheGag protein is not efficiently cleaved into the mature viralproteins seen in most other retroviruses, leading to the imma-ture morphology. The Pol precursor protein is only partiallycleaved; the integrase domain is removed by viral protease, butthe protease and reverse transcriptase domains apparently arefound in the same molecule. The Env protein is cleaved intosurface and transmembrane domains, as in other retroviruses.However, the Env protein contains an endoplasmic reticulumretention signal which contributes to its site of budding (39).

Viral Life Cycle

FV replication differs from that of conventional retroviruseslike type C oncoviruses and lentiviruses in many, sometimesremarkable, ways. Interestingly, in some respects FV replica-

tion more closely resembles that of the other family of reversetranscriptase-encoding viruses, the Hepadnaviridae (reviewedin reference 63). An outline of the FV life cycle is given in Fig.3. Some of the unique aspects of FV replication are denotedwith red text and arrows, while those shared by FV and con-ventional retroviruses such as human immunodeficiency virus(HIV) are denoted in black. Reverse transcription occurs at alate step in the replication cycle, resulting in infectiousSFVcpz(hu) particles containing DNA rather than RNA (79,130). Efforts to strictly classify FV as either DNA or RNAviruses are problematic. Although the infectious genome ofSFVcpz(hu) is DNA, viral RNA is specifically packaged intovirions (Fig 3). Furthermore, only SFVcpz(hu) isolates havebeen shown to contain an infectious DNA genome. Duringviral maturation, cleavage of the Gag protein by viral proteaseis incomplete, and mature particles do not contain matrix,capsid, and nucleocapsid proteins but instead comprise twolarge Gag proteins differing by ca. 4 kDa at the carboxy ter-minus. Particles bud from cells primarily through the endo-plasmic reticulum (37, 38), and in the absence of Env glycop-roteins, particles are not released from cells (14, 31). Thecellular receptor for FV infection is not known but must beubiquitous, since FV have wide tropism (see below).

In Vitro Tropism

In vitro, FV can infect most cell types from a wide variety ofspecies (47, 76). However, the result of infection can be mark-edly different depending on the cell type. Infection of many celltypes leads to the outcome resulting in the characteristic foamycell appearance which gives these viruses their name. Infectedcells undergo rapid syncytium formation, cytoplasmic vacuol-ization, and cell death. Fibroblast cell lines such as humanembryonic lung cells, baby hamster kidney cells, and Mus dunnitail fibroblasts are particularly sensitive to the cytopathic ef-fects (CPE) of FV infection.

In contrast, it is possible to chronically infect a variety ofcells lines in culture. Transformed cell lines of myeloid, ery-throid, and lymphoid origin have all been persistently infected(76, 78, 129). However, primary human lymphoid cells werefound to be sensitive to the FV CPE, while in contrast, mono-cytes were infected with FV but showed no CPE (78). Chronicinfections in vitro result in continual virus production in theabsence of notable cell death but, compared to cytopathicinfections, produce significantly lower viral titers (129). Thefactors, either viral or host, which mediate a lytic versuschronic infection in vitro are not well understood. A number ofreports indicate that increased expression of Bet may enablechronic infection (93, 95, 127) as well as block superinfection(16). However, the role of Bet in establishment of a chronicinfection is not completely clear, as Bet2 viruses can alsoestablish chronic infections in vivo (21).

NATURAL HISTORY

The first description of an FV was published in 1954, whenit was found as a contaminant in primary monkey kidney cul-tures (27). The first isolate of this “foamy viral agent” wasobtained in 1955 (91). Shortly thereafter, FV were isolatedfrom a wide variety of New and Old World monkeys, cats,cows, and prosimians (Table 1).

FIG. 1. Electron microscopy of SFVcpz(hu)-infected human em-bryonic lung fibroblasts. (A) Preassembled core budding through theplasma membrane. (B) Preassembled cores accumulating in cytoplasmof cell and budding into intracellular membranes such as the endo-plasmic reticulum. Note the spiked Env projections and the absence offurther maturation of viral cores after budding through membranes.Bars, 100 mm.

166 MEIERING AND LINIAL CLIN. MICROBIOL. REV.


http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

Origin of “Human” FV

It was not until 1971 that a putative human FV was isolated.In this case, a viral agent with FV-like characteristics wasisolated from lymphoblastoid cells released from a human na-sopharyngeal carcinoma (NPC) isolated from a Kenyan patient(3). This isolate was termed human FV because of its originand became the prototypic laboratory strain when it was sub-sequently sequenced and infectious molecular clones were de-rived (68, 85, 86). Shortly after the isolation of SFVcpz(hu),the original authors concluded that SFVcpz(hu) was a distincttype of FV most closely related to Simian FV (SFV) types 6and 7, both isolated from chimpanzees (28). In a contradictoryreport, Brown et al. concluded that SFVcpz(hu) was not adistinct type of FV but rather a variant strain of chimpanzeeFV (20). The origin of SFVcpz(hu) was debated until 1994,when SFVcpz was cloned and sequenced (46). The sequenceshowed that there is 86 to 95% amino acid identity betweenSFVcpz and SFVcpz(hu) (46), indicating that SFVcpz(hu) islikely a variant of SFVcpz and not a unique isolate. Furtherphylogenetic analysis of the pol regions of these genomes in-dicate 89 to 92% nucleotide homology and 95 to 97% aminoacid homology between SFVcpz(hu) and the various SFVcpzstrains (101). Recently, sequence comparisons between theoriginal SFVcpz(hu) isolate and SFV from four distinct sub-species of chimpanzee demonstrate that SFVcpz(hu) is mostclosely related to FV from Pan troglodytes schweinfurthii, whosenatural habitat includes Kenya (W. Heneine, W. M. Switzer, G.Shanmugam, P. Sandstrom, J. Ely, M. Peeters, L. Chapman,and T. M. Folks, submitted for publication). Taken together,these results clearly indicate that SFVcpz(hu) is a variant FVof chimpanzee origin. Since the individual from whomSFVcpz(hu) was isolated lived in proximity to P. troglodytesschweinfurthii, it is possible that the virus was acquired as azoonotic infection. However, it is not possible to rule outlaboratory contamination as the source of SFVcpz(hu).

FV Prevalence

The prevalence of FV infection in naturally infected animalsis generally high and varies widely depending on the speciesand environmental conditions (Table 1). Some species, such asrhesus macaques (58), African green monkeys (102), chimpan-zees (52), and cats (124), harbor closely related yet serologi-cally distinct subtypes of FV. Seroprevalence is generallyhigher in animals housed in captivity, reaching 100% com-pared to animals studied in the wild. For example, a 1995 studyshowed that 93% of African green monkeys housed in captivitywere infected with FV (103), while only 36% of wild animalstested positive in a separate study (109). The prevalence datapresented in Table 1 indicate that FV efficiently infect not onlynonhuman primates but cats and cows as well. UnconfirmedFV infections have also been reported for hamsters (53), sheep(32), and sea lions (59).

FV Transmission

The precise mechanisms of FV transmission are not wellunderstood. However, the data collected thus far indicate thata saliva-based means of transmission, such as licking or biting,is most probable. The earliest controlled study of FV trans-mission was conducted in cattle, in which bovine FV (BFV)infection is endemic (55). This study showed that newborncalves had passive immunity, which was lost by 3 to 5 monthsof age. All calves were BFV negative at birth, but once placedin contact with infected adults, approximately 35% becameinfected within 10 weeks and 85% by 3 years. A similar studywas performed with captive baboons (18). As in cattle, infantswere initially FV negative and had passive maternal antibody.By 15 months of age, 1 of 10 juveniles tested positive for FV.When adults were analyzed, 100% tested positive. Addition-ally, SFV antibodies can be found in juvenile animals prior tosexual maturity, indicating a nonsexual route of transmission(J. Allan, personal communication).

FIG. 2. Schematic representation of SFVcpz(hu) genome and viral RNAs. (A) Genome of SFVcpz (hu) showing the location of gag, pol, env,tas (bel-1), bet, bel-2, and the putative bel-3 genes. Cross-hatched box indicates location of the IP. Half-arrows indicate transcription start sites forthe LTR and IP. (B) Major RNAs produced in SFVcpz(hu)-infected cells. mRNAs are represented by solid lines, and ORFs are represented byrectangles. Multiple rectangles on bet mRNA indicate a spliced message.

VOL. 14, 2001 FOAMY VIRUS EPIDEMIOLOGY AND INFECTION 167


http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

Recently, a comprehensive study of feline FV (FFV) infec-tion in age and sex-matched domestic and feral cats was per-formed (125). In domestic cats, the study found a gradualincrease in FFV infection over time, but no differences be-tween males (56%) and females (57%). Feline immunodefi-ciency virus (FIV) infection, however, was significantly higherin male cats (16%) and highest in nondesexed males (35%),consistent with aggressive behavior, such as biting, as a modeof transmission. When feral cats were analyzed, FFV infectionwas lower in males (23%) than females (52%), while FIVinfection was higher in males (14%) than in females (3%).FFV transmission does not correlate well with aggressive orsexual behavior but does correlate well with nonaggressivesocial behavior, such as grooming.

ANIMAL MODELS OF FV INFECTION

As early as 1955, Rustigian et al. infected monkeys, rabbits,chicks, and mice with “foamy agents” from rhesus macaquekidney cultures (91). Disease was demonstrated in newborn

mice, but because the authors were attempting to adapt Den-gue virus to monkey cells, it is likely that this result was due toDengue virus infection and not FV.

Rabbits

In 1974, Johnston infected rabbits with SFVmac via intra-dermal inoculation (57). The only pathology noted by the au-thor was inflammation and necrosis at the site of injection.Very low titer virus could be recovered from the dermal lesionsas well as from tissue kidney explant cultures up to 1 yearpostinfection. A second study of SFVmac infection of rabbitswas performed by Swack and Hsuing in 1975 (112). This reportdemonstrated that rabbits could be inoculated by either intra-peritoneal or intranasal inoculation. Virus could be recoveredat all time points up to 264 days postinfection by cocultivationfrom spleen, liver, kidney, lung, salivary gland, brain, and bloodcells, but never from serum. Tissue distribution of FV in theexperimentally infected rabbits mirrored that of naturally in-fected macaques and baboons (see below). Neutralizing anti-

FIG. 3. Comparison of FV and conventional retroviral life cycles. The nucleus is shown in yellow, and the endoplasmic reticulum (ER) is shownin gray. DNA genomes are represented by blue bars, and RNA genomes are represented by curved red lines. Characteristics specific to the FVlife cycle are denoted by red text and arrows. Features common to both FV and conventional life cycles are shown with black text and arrows. Bluetext and arrows represent events which are specific to conventional retroviruses. aFV and conventional type-D retroviruses assemble cores in thecytoplasm, while viruses such as HIV do not, but instead assemble at the plasma membrane. bFV have been shown to bud through the plasmamembrane, but the majority of infectious virus buds through the endoplasmic reticulum. Processes denoted with a question mark are believed tooccur, but have not been proven. The precise timing of reverse transcription is not known, but for SFVcpz(hu) it occurs late in the viral life cycleand is completed before viral adsorption.



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

body titers were low at all time points but increased over time.No pathology was noted in any of the FV-infected animals.Another study performed in 1979 investigated whetherSFVcpz induces immunosuppression in rabbits (49). Again, nopathology was noted in any animals, but a transient immuno-suppressive effect in the absence of interferon production wasobserved in infected rabbits. Another study of FV-inducedimmunosuppression in rabbits and mice was published in 1993(96). Similar to the previous study but using in vitro prolifer-ation assays, the authors observed a transient immunosuppres-sive effect only in FV-infected animals. No animals showed anysign of disease, and FV was only recovered after coculture onpermissive cells.

Recently, a long-term study of SFVcpz(hu)-infected rabbitswas performed (94). In this 5-year study, all animals developedrobust antibody responses against all major FV proteins. FVwas recovered from peripheral blood leukocytes (PBL) by co-culture after 2 weeks, and all major organs were positive forFV by nested PCR. FV was never detected in freshly isolatedPBL by indirect immunofluorescence (IFA) or by electronmicroscopy, despite the fact that the same cells yielded FVwhen cocultured on permissive cells. As in other studies, therewas no gross pathology or histopathological lesions in any ofthe infected animals.

Mice

There are two published studies using mice as a modelsystem for FV infection. The first employed SFVcpz (type 6)and Swiss-Webster mice (19). As in previous studies with rab-bits, all animals were asymptomatic throughout the course ofthe experiment. Virus was recovered from spleen and kidneyby coculture, but histological examination and indirect immu-nofluorescence of the same tissues were negative. A morerecent study utilized a variety of inbred mouse species and theprototype SFVcpz(hu) (98). A differential humoral immuneresponse was observed between CBA/Ca and C57BL/6 mice,wherein both developed antibody against Gag protein but onlyC57BL/6 mice produced antibody against the Bet protein. Theauthors note that FV was detected in a wide variety of organsby nested PCR and that the frequency of detection increased

over time in CBA/Ca mice but decreased over time in C57BL/6animals. Unlike the previous study using Swiss-Webster mice,recovery of FV from infected mice by coculture was very inef-ficient. Like the previous study, no pathology was observedthroughout the experiment.

Transgenic Mice

In an effort to understand the pathogenic potential of FV,two transgenic strains of mice were generated (17). The firstexpressed all SFVcpz(hu) genes from the LTR but was repli-cation defective due to a frameshift in the integrase domain ofpol. A second strain contained deletions in gag, pol, and env,expressing only the accessory genes tas and bet from the IP. Inboth cases, clinical symptoms, which eventually proved fatal,included ataxia, spastic tetraparesis, and blindness. The rate ofdisease progression, however, was faster in animals expressingall FV genes. In affected animals, transgene expression waslimited to the forebrain and cerebellum. Pathology in all af-fected animals was limited to tissues of the central nervoussystem (CNS) and striated muscle. At the onset of symptomsthere was progressive degeneration of primarily the CA3 re-gion of the hippocampus and the telencephalic cortex. Someanimals showed degeneration of striated muscle as well. Inter-estingly, transgene expression was observed in only a fractionof the cells of a given lineage. This is unusual for transgenesand indicates that cell type-specific factors are likely requiredfor FV expression. The gene products which were responsiblefor the pathology were not identified, but it was likely to be tasand/or bet because these are the only intact open readingframes (ORFs) in both viral constructs.

A possible explanation for the observation that mice ex-pressing FV structural genes progressed more rapidly thanthose which only expressed tas and bet was provided by analysisof FV protein expression in affected animals (8). It was notedthat in both transgenic strains Tas expression was observed, butonly in cells expressing FV structural genes was there syncy-tium formation in astrocytes. The fusogenic property is likelydue to expression of FV Env. Env expression may acceleratedisease progression because of its fusogenic property per se orbecause by fusing Tas-expressing cells with neighboring cells,

TABLE 1. FV isolates and prevalence

Species Virus isolate(conventional designations)

Year firstisolated

Prevalence(%)a References

Rhesus macaque (Macaca mulatta, M. fascicularis) SFVmac (SFV-1, SFV-2) 1955 10–100 50, 58, 91, 103, 109African green monkey (Cercopthieus aethiops) SFVagm (SFV-3) 1964 28–93 50, 103, 109, 110Squirrel monkey (Saimiri sciureus) SFVsqu (SFV-4) 1971 63 50, 56Galago (Galago crassicaudatus panganiensis) SFVgal (SFV-5) 1971 83 50, 56Chimpanzee (Pan troglodytes sp.) SFVcpz (SFV-6, SFV-7) 1967 75–90 20, 50, 52, 89Spider monkey (Ateles sp.) SFVspm (SFV-8) 1973 61 51Capuchin (Cebus sp.) SFVcap (SFV-9) 1975 ND 50Baboon (Papio cynocephalus) SFVbab (SFV-10) 1975 34–100 4, 18, 41, 50Orangutan (Pongo pymaeus) SFVora (SFV-11) 1994 26–100 50, 74Gorilla (Gorilla gorilla sp.) SFVgor (SFVgg) 1995 ND 15Feline FFV (FeFV) 1969 33–76 25, 35, 88, 124, 125Bovine BFV (BSV) 1969 40–85 54, 55, 72Equine EFV 1999 ND 114Marmoset (Callithrix jacchus) SFVmar 1981 54 73Human SVFcpz(hu) (HFV, HFVhu, CFV/hu) 1971 N/A 3

a Prevalence may include results from multiple studies and different animal populations. ND, not determined. N/A, not applicable.



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

Tas can induce FV expression in those neighboring cells whichotherwise would have not expressed any FV genes.

Further work was performed investigating transgene expres-sion during development (6). These authors determined thatduring embyrogenesis the transgene was broadly expressed,albeit at low levels, in tissues of ectodermal and mesodermalorigin, but this expression waned as animals neared gestation.Perinatal expression of the transgene was restricted to theCNS, and by 3 weeks of age, transgene expression was unde-tectable. In young adult mice, transgene expression reappearedin the CNS and striated muscle and reached levels much higherthan observed during embyrogenesis. Interestingly, the authorsnoted that transgene expression in adult mice was invariablyhigh, but the cellular distribution was variable even amonglittermates. These results are most likely explained by the pos-itive-feedback loop created whereby the transactivator, Tas,activates its own promoter as well as the LTR (67, 87). Hence,if a basal level of tas expression is present, the result is anunregulated positive feedback loop.

Transgenic mice containing the tas and bet ORFs undercontrol of the LTR were generated in an attempt to determinewhich gene(s) was responsible for the neurotoxicity observedin the previous studies (116). None of these animals showeddisease progression despite the presence of mRNA corre-

sponding to both tas and bet forms in a wide variety of tissues,including the CNS. Interestingly, only Tas protein was detectedin the brains of these animals, while affected animals from theprevious studies expressed not only Tas, but also high levels ofBet. These data indicate that Bet expression may be requiredfor disease progression in transgenic mice.

Taken together, the studies in transgenic animals haveclearly demonstrated the pathogenic potential of FV gene ex-pression when it is targeted to the brain and striated muscle.They have also shown that expression of structural genes en-hances pathogenicity and that Bet may be responsible for thepathology. However, whether FV can productively infect thetissues in which pathology is seen in transgenic animals duringa natural infection remains unclear. The results of the majorityof these studies are reviewed in detail elsewhere (5, 7).

FV INFECTION AND HUMAN DISEASE

Since the discovery of FV, and especially since the isolationof SFVcpz(hu), researchers have searched for diseases associ-ated with FV infection in humans. A wide variety of diseaseshave been tenuously associated with FV infection of humans(Table 2). Most of these studies have relied upon only oneassay to demonstrate FV infection, leading to the possibility of

TABLE 2. Summary of studies examining disease association with FV infections in humans

Disease No. of positivesamples/total Methodsa Disease

associationb Reference(s)

Thyroiditis de Quervain 1/1 CC FS Stancek et al. (106)5/8 CC, IFA, NAB FS Stancek et al. (107)6

dIFA, EM Yes Werner et al. (119)

0/19 IFA, RIPA, WB, ELISA No Debons-Guillemin et al. (26)0/58 IFA, RIPA, WB, PCR No Schweizer et al. (103)

Graves’ disease 7/7 IFA FS Wick et al. (122, 123)19/29 SB, PCR Yes Lagaye et al. (61)0/41 SB, PCR No Schweizer et al. (104)4/4c

5/99 PCR No Yanagawa et al. (128)0/45 ELISA, WB No Mahnke et al. (71)0/28 IFA, RIPA, WB, PCR No Schweizer et al. (103)

13/24 PCR Yes Lee et al. (62)

Multiple sclerosis 33/85 ELISA FS Westarp et al. (120, 121)0/11 CC, PCR No Svenningsson et al. (111)0/48 ELISA, WB No Mahnke et al. (71)2/60 ELISA No Lycke et al. (70)0/34 IFA No Rosener et al. (90)

Myasthenia gravis 1/1 WB Yes Saib et al. (92)4/4 PCR, NAB FS Liu et al. (64)

Chronic fatigue syndrome 0/41 ELISA, WB No Mahnke et al. (71)0/30 WB, IFA No Gow et al. (40)

Familial Mediterranean fever 3/3 PCR, SB Yes Tamura et al. (113)

Sensorineural hearing loss 4/30 IFA FS Pyykko et al. (84)

Dialysis encephalopathy 1/1 CC FS Cameron et al. (22)

a CC, coculture methods. EM, electron microscopy.b Possibility of disease association with FV infection as reported in the references. Yes, association observed; No, no association observed; FS, further study merited.c DNA from these four patient samples was the same as used earlier (61) but reanalyzed (104).d Agent isolated by Stancek and Gressnerova further characterized by Werner and Gelderblom (119).



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

spurious positive results. In most cases, more comprehensivestudies using multiple assays to confirm virus presence havefailed to verify the initial disease association.

Thyroiditis de Quervain

A transmissible agent was associated with thyroditis deQuervain in 1974 by coculturing of patient samples with sus-ceptible cell lines (106, 107). The agent was later studied byelectron microscopy and tentatively classified as a paramyxo-virus (105). Subsequently, the agent was reanalyzed by immu-nofluorescence and electron microscopy and reclassified as anFV (119). A more comprehensive study using IFA, radioim-munoprecipitation (RIPA), Western blot (WB), and enzyme-linked immunoabsorbent assay (ELISA) on samples from 19patients demonstrated no association between FV infectionand thyroiditis de Quervain (26). As part of a larger studyinvestigating the prevalence of FV infection in humans, 59patients with thyroid disorders, including 28 with Quervain’sthyroiditis, were analyzed by IFA, RIPA, WB, and PCR (103).Again, there was no prevalence of FV infection in thyroiditisde Quervain patients. The origin of the FV-like agent in theoriginal publications (106, 107) remains unclear, but becausethe more comprehensive study was unable to detect FV infec-tion in Quervain patients, it is highly unlikely that FV infectionis a causative agent of this condition.

Graves’ Disease

A putative association of FV infection with Graves’ disease(GD) was first reported by Wick et al. in 1992 (122, 123). Usingantibodies against FV Gag protein, the authors detected asignal by IFA in tissue sections from GD patients. A secondstudy of French GD patients revealed the presence of FVDNA by PCR in 19 of 29 patients (61). DNA samples fromthese patients as well as samples from 41 German GD patientswere subsequently analyzed by Southern blot and PCR (104).This study confirmed the presence of FV DNA in the Frenchcohort but did not detect FV DNA in any of the 41 Germanpatients. This leaves open the possibility of artifactual contam-ination of the French samples. Another study analyzed 28more GD patients, this time using IFA, RIPA, and WB and didnot detect FV markers in any samples (43). In a separate study,5 of 99 GD patient samples were positive for FV sequenceswhen analyzed by PCR (128). However, 6 of 109 control pa-tients also tested positive using this assay, indicating no statis-tical association between the presence of FV sequences andGD. As part of a study investigating the presence of FV anti-body in African patients, serum from 45 patients was analyzedby ELISA and WB (71). None of the GD patients had FV-reactive antibodies using these assays. Recently, nested PCRwas used to identify FV gag, env, and LTR sequences in normaland Korean GD patients. FV sequences were detected in 13 of24 patients, and in 7 patients all three regions were amplified(62). However, 9 of 23 apparently normal controls were alsopositive for at least one locus under the same conditions. Al-though intriguing, as no other methods were used to confirmFV infection, these studies provide no evidence for a causativerole for FV in GD. However, the data do represent the possi-bility that FV-like sequences may be present in some geo-graphically distinct populations.

Multiple Sclerosis

The long search for an etiologic agent in multiple sclerosis(MS) and the findings of neurodegenerative disease in trans-genic mice expressing FV genes led to an idea that FV infec-tion may be associated with MS. Westarp et al. used an ELISA-based technique to analyze the sera of more than 85 MSpatients for the presence of FV-specific antibodies (120, 121).The authors found that sera from 33 of 85 patients cross-reacted with FV antigen and concluded that there may be alink between FV infection and MS pathology. In four subse-quent studies, 153 patient samples were analyzed using a va-riety of techniques, including coculture, PCR, ELISA, WB,and IFA (70, 71, 90, 111). Only in cases which relied exclusivelyon the ELISA technique was there any indication of FV infec-tion in MS patients. However, except for the original studies byWestarp et al., these studies all reached the conclusion thatthere is no association between FV infection and MS.

Myasthenia Gravis

The cross-reactivity of a patient serum sample with FV an-tigen by WB led to the speculation that FV infection may beinvolved in myasthenia gravis (92). A more recent study of fourmyasthenia gravis patients showed the presence of FV DNA inpatient thymuses by PCR and Southern blot as well as lowlevels of SFVcpz(hu)-specific neutralizing antibody in all pa-tients (64). The authors of this study were unable to recoverinfectious FV from these patients, and their Southern blot dataindicate that the FV sequences detected may be from incom-plete proviruses. For these reasons, the authors suggest theneed for further study to confirm or refute the role of FV as anetiological agent in myasthenia gravis. No further confirmatorystudies have been published to date.

Other Diseases

FV has also been investigated as an etiologic agent in avariety of other diseases. Two studies in 1992 searched forFV-specific antibodies in patients with chronic fatigue syn-drome (40, 71). In both studies the authors were unable to findFV seroreactivity in 71 samples tested. A number of uncon-firmed reports, largely based on single assays, have implicatedFV infection in familial Mediterranean fever (113), sensori-neural hearing loss (84), and dialysis encephalopathy (22).

As a whole these studies clearly demonstrate that the linkbetween FV infection and human disease is unfounded. Theonly exception is myasthenia gravis, but the inability to isolateFV from myasthenia gravis patients confounds the issue. Theability to amplify FV-like sequences from human DNA byPCR is used by many as evidence for FV infection, but may beexplained by the sequence homology of FV with other retro-viruses. Phylogenetic analyses indicate that FV are distantlyrelated to other complex retroviruses, like human T-cell lym-photrophic virus (HTLV) and HIV, but most closely related tohuman endogenous retrovirus type L, which may be present atup to 200 copies per cell in the human genome (24). Further-more, the probability of FV as an etiologic agent in humandisease is further reduced because controlled studies have in-dicated there is no evidence of FV infection in the humanpopulation (see below).



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

FV PREVALENCE IN HUMANS

Early Serological Studies

In conjunction with the search for human diseases associ-ated with FV infection, a number of studies attempted todetermine whether any specific human populations are natu-rally infected with SFVcpz(hu). The study which first hintedthat the so-called human FV isolate was not of human originalso demonstrated by serology that FV infection was not prev-alent in humans (20). More than 250 patient samples wereassayed, including 50 from individuals with NPC and Burkitt’slymphoma. None of these were found to contain neutralizingantibodies specific for SFVcpz(hu). The same group alsotested 14 animal caretakers and 24 laboratory personnel, all ofwhom had regular contact with nonhuman primates, and foundthat none carried anti-FV antibodies as measured using IFAand neutralizing antibody (NAB) tests. Three seroepidemio-logical studies by Achong and Epstein (1,2) and by Muller et al.(80) sought to confirm or refute the negative data obtained byBrown et al. (20) and by Nemo et al. (82). In these studies,samples were analyzed from over 800 individuals from variousregions of Africa, as well as Singapore and Britain. Using IFAanalysis of FV-infected cells, it was found that while healthyEast African patients have a low seroprevalence (;4%), EastAfricans with tumors, especially NPC, were .20% seropositiveusing this assay. No samples obtained from individuals outsidethe regions of East Africa studied, including Tunisia, wereseropositive. At about the same time, a study of over 1,700persons from various Pacific island territories was performedusing IFA and NAB methods (69). Overall, 6.9% of the pop-ulation showed FV-specific antibodies by IFA, with up to 15%of some individual populations testing positive. The presenceof NAB correlated well with the IFA data. In another study,ELISA as well as WB techniques were used to analyze 3,020serum samples from African and European patients (71).Overall, 3.2% were seropositive using these techniques. Only1.6% of European samples were positive, while 6.3% of sam-ples from East Africa were positive. A seroprevalence of 16.6%in patients with NPC was in accordance with previous studies.

Epidemiological Studies

Two comprehensive studies were performed in 1995 and1996 which cast doubt on the conclusion of previous studieswhich had suggested that FV infections are prevalent in somehuman populations. The first used WB, RIPA, IFA, and PCRto screen over 2,500 serum samples from Germany and eastand west Africa (103). Sera from patients with a variety ofdiseases and conditions, including various cancers, thyroid dis-orders, AIDS, malaria, sudden deafness, graft-related immu-nosuppression, and other autoimmune disorders, were in-cluded in the study. This study differed from previous studies inthat samples from FV-infected animals as well as accidentallyinfected and zoonotically infected humans were used to estab-lish the baseline criteria for an authentic FV infection. Patientsamples had to test positive in all four assays to be consideredFV infected. Control experiments showed that 80% of rhesusmonkeys, 93% of African green monkeys, 75% of chimpan-zees, and two humans with documented infection by FV werepositive for FV in all serological assays. When PCR was per-

formed on 32 human and primate subjects, 14 samples testedpositive. In these 14 cases, all serological results were alsopositive, while the 18 cases that were negative by PCR werealso negative by serology. Tests of unknown sera indicated that99.7% of the samples were negative in at least one of theserological assays. It is important to note that a significantproportion of the test sera were positive by one or two of theserological assays, but only 7 of 2,688 samples were positive forall three, and in all these cases the WB results were question-able. However, the rate of false-positive results seen in thisstudy when using only a single serological assay could readilyexplain the apparent positive results observed in previous stud-ies which relied upon only one or two serological assays. Asecond comprehensive study using sample from diverse geo-graphic regions was performed using ELISA as a preliminaryscreen (9). ELISA-positive samples were then tested by focalimmunoassay, WB, NAB, and, when possible, PCR. The initialscreen by ELISA produced results similar to previous studies,in that 17% of Pacific Islanders and 34% of samples fromMalawi in central Africa were positive. However, when sub-jected to further analyses, none of these samples were positiveusing the confirmation techniques. Taken together, these well-controlled studies indicate that FV infections are not prevalentin the human population.

Zoonotic Infections

In an effort to understand the risk of zoonotic transmissionof FV in a natural setting, Goepfert et al. examined the prev-alence of FV infection in West African hunters (36). Thiscohort is presumably at high risk for zoonotic transmission ofFV because of the close contact with body fluid and tissue froma wide variety of nonhuman primates. Using a recombinantRIPA and PCR techniques, none of the 17 hunters examinedtested positive for FV infection.

Another group at high risk for zoonotic transmission of SFVis frequent handlers of nonhuman primates, such as veterinar-ians and zookeepers. A voluntary study sponsored by the Cen-ters for Disease Control tested animal handlers for simianimmunodeficiency virus, simian T-cell lymphotrophic virus,and simian type D retrovirus as well as SFV infection. Theresults of this study show that 3 of the 231 participants testedpositive for FV infection (13). A virus characteristic of FV wasisolated from one of the three individuals by coculture ofperipheral blood mononuclear cells (PBMC) on permissivecells. Virus from this caretaker was subsequently determinedto be of SFVagm origin (100). PBL from this individual weresorted by fluorescence-activated cell sorting (FACS) and thentested for FV DNA by nested PCR. This analysis determinedthat CD81 T cells were the major cellular reservoir infectedwith FV (117). A follow-up study identified a fourth individualinfected with FV and confirmed the three previous zoonoticinfections (44). In this study, sequence analysis of PCR prod-ucts indicated that one individual was infected with SFVagm,while the remaining three were infected with SFVbab. In allcases, the positive individuals have histories of severe bitewounds or, in one case, two instances of instrument puncturewounds. Archived serum samples from one worker showed thepresence of anti-FV antibodies dating to 1978, while thosefrom another dated to 1988. In no cases have associated clin-



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

ical symptoms been reported. Sexual transmission was not ob-served in any of the cases, nor was there transmission to im-mediate family members.

It should be noted that there are no published studies on thepresence of other primate FV in the general population, norare there studies on the transmission of nonprimate virusessuch as FFV to humans.

Baboon Liver Transplants

Transmission of SFVbab to humans was studied in two pa-tients who had received baboon liver transplants (11, 12). Thetwo patients had AIDS and end-stage hepatic disease associ-ated with hepatitis B virus infection. Both patients receivedbaboon livers, and both died shortly afterwards from compli-cations unrelated to FV infection (108). Using PCR, SFVbabsequences were detected in various organs from both patients.In addition, baboon endogenous virus was also detected in awide variety of organs at distal locations from the site of trans-plant. The presence of baboon mitochondrial DNA in thesame locations suggests that the viral sequences were presentin donor cells, possibly baboon leukocytes, which had migratedto distant sites in the recipients. However, infection of thehuman cells was not specifically analyzed. No SFVbab viruscould be isolated from either patient.

FV PERSISTENCE

Isolation from Infected Individuals

Persistence in the absence of disease is the defining charac-teristic of natural, accidental, and experimental FV infection.Despite the presence of a robust antibody response against FV,infectious virus from infected animals can be easily recoveredby coculturing throat swabbings, PBMC, or infected tissue withsusceptible cell lines (50, 55, 56, 60). The recovery of virus fromcross-species and experimental infections is more difficult andcan only be achieved by coculture of PBMC or infected tissues,but interestingly not from saliva. However, the recovery ofinfectious SFVagm from an accidentally infected human after20 years, despite high antibody titers, underscores the ability ofFV to persist for long periods of time even in cross-speciestransmissions (44, 100). An SFVagm virus isolated from theinfected person was found to lack a functional bet gene, whichconfounds the evidence for the role of the bet gene in in vivopersistence (21).

It is important to note the incredible genetic stability of FVcompared to other retroviruses. For example, in one case ofSFVcpz infection of a veterinarian who had been severelybitten by a chimpanzee, the viral sequences in the human andchimp could be compared 15 years after the zoonosis. Very fewnucleotide differences could be detected in the integrase do-main of pol by PCR and sequencing (Heneine et al., submit-ted). A study of the genetic stability of African green monkeysinfected with FV also found remarkably high homology rates(102). In one animal, sequence analysis from samples takenover a 13-year period indicated homology rates of 99.5 to100%. These data clearly reflect the very low replication rate ofFV in vivo, similar to the case of HTLV.

Sites of Viral Persistence

The tropism of FV in vivo appears to be very broad. Usingcoculture techniques as well as PCR, FV can be detected inmost tissues in infected animals (30, 50). In contrast, however,the direct culture of FV from sera and the detection of repli-cating FV in infected tissues using IFA and electron micros-copy have been consistently negative (19, 49, 50, 112). In arecent study of naturally infected African green monkeys,nested PCR identified proviral FV DNA in all organs tested(30). To detect sites of active viral replication, reverse tran-scriptase-PCR analysis was performed on RNA from the sameorgans. Only in the oral mucosa of a single animal was apositive reverse transcriptase-PCR result observed. This resultwas confirmed by in situ hybridization using an env-specificprobe. This location is consistent with our limited knowledgeof FV transmission, which appears to be through saliva. Theability of the authors to find integrated FV DNA by PCR inevery organ tested highlights the central paradox of FV biol-ogy: the processes of FV infection, dissemination, both intra-and interhost, and persistence are very efficient despite theapparent absence of viral replication in infected tissues. It isimportant to note that detection of FV DNA in a particulartissue does not indicate that the tissue is infected per se. In-fection of a circulating population of cells could account forsuch PCR results. Nevertheless, the mechanism(s) which un-derlies the process of virus dissemination in vivo is poorlyunderstood, and this underscores the importance of determin-ing the actual cell type(s) in which FV can persist and replicate.Investigations of both the host immunological and viral factorsinvolved in FV persistence also need to be undertaken.

A number of studies have sought to identify which subset(s)of peripheral blood cells is persistently infected in FV-infectedhosts. PBL from naturally infected African green monkeys,chimpanzees, and two accidentally infected humans were an-alyzed for the presence of FV DNA. One human was acciden-tally infected with the prototype lab strain, SFVcpz(hu), whilethe second was infected zoonotically with SFVagm. PBL fromthese individuals were separated into PBMC and polymorpho-nuclear leukocytes (PMNL), then positively sorted by FACSinto CD81, CD41, and CD141 (monocyte) populations. Hu-man samples were also sorted for CD191 (B cells) cells, whilefor African green monkeys and chimpanzee, CD42 CD82 frac-tions, mostly B cells, were collected. CD81 cells from all sub-jects were positive for FV DNA. All other human cell typeswere negative for FV DNA. However in monkey samples, 4 of7 CD41 samples, 10 of 13 CD42 CD82samples, 3 of 11 CD141

samples, and 4 of 11 PMNL samples tested positive.A second study attempting to identify the cellular tropism of

FV was performed on PBMC from a human accidentally in-fected with SFVagm (21). Virus isolated from this individualwas determined to have a defective bel-2 ORF and thus apresumably defective bet gene. Antibody-conjugated magneticbeads were used to positively sort PBMC into CD4, CD8,CD14, and CD19 populations. Nested PCR on DNA fromthese populations indicated that CD141 and CDI91 popula-tions were infected, while CD41 and CD81 cells were notinfected. These results directly contradict the results obtainedby Von Laer et al. (117). In both studies, humans infected withSFVagm were analyzed, and thus one possible explanation for



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

these contradictory results is that an intact bel-2 ORF some-how alters tropism in vivo. Clearly, further investigation of thein vivo cellular targets of FV is needed.

VECTORS

The characteristics of FV infection, such as lack of patho-genicity, broad host range, and wide tissue tropism, persistencein the presence of neutralizing antibody, and the large genomesize, make FV attractive vectors for gene therapy. There isevidence that FV vectors can infect CD341 hematopoietic cellsmore efficiently than murine leukemia virus based vectors (48).The apparent lack of pathogenicity provides the option ofusing replication-competent vectors in which the bet gene canbe replaced with a promoter and gene of interest (99). Viruseswhich lack the transactivator tas can be constructed by replac-ing the U3 region of the LTR with constitutive promoters suchas that from cytomegalovirus (97, 115). However, several prob-lems need to be overcome. Currently, there are no highlyefficient packaging cell lines for FV, and the apparent inabilityto pseudotype FV particle with other envelopes is problematic(83, 126). In addition, the vector systems which have beenreported have relatively low titers (115, 126). Furthermore,several reports have described multiple cis-acting sequences inthe FV genome that are required for vector transfer (29, 42).The first packaging signal is located at the 59 end of the RNA,and a second is located near the 39 end of the pol gene. Abetter understanding of these cis-acting elements is requiredfor optimal vector and packaging cell line construction. Afurther unknown is whether viral vectors will continue to beexpressed at long times after administration.

CONCLUSIONS

To date, except for the FV, all retroviruses have been shownto cause disease in some host, either naturally or accidentallyinfected. Simple retroviruses such as murine leukemia virusand avian leukosis virus induce tumors and/or immunodefi-ciencies with long latency periods. Complex retroviruses likebovine leukemia virus, HTLV, and HIV can also be highlypathogenic. Most simian immunodeficiency viruses are non-pathogenic in their natural hosts but can cause rapid, fataldisease when cross-species infection occurs. There is mountingevidence that both HIV-1 and HIV-2 have been introducedinto the human population via zoonotic transmission on mul-tiple occasions (33, 34, 81). Human FV has been described as“a virus in search of a disease” (118). However, as mentioned,many viruses persist in their natural hosts in the absence ofdisease only to reveal their true pathogenic potential whenthey cross species barriers. Despite evidence to the contraryregarding FV zoonosis, great caution should taken when pur-posefully introducing viruses or vectors into new host species.In our opinion, even greater caution should be taken in per-forming xenotransplantations using organs from foreign spe-cies which are known to harbor endogenous or naturally oc-curring viruses. Use of primate material for production ofbiologicals, such as vaccines, could also inadvertently introduceFV into the human population. Our knowledge to date indi-cates that FV are truly nonpathogenic, even in other hostspecies; however, very few transmission to humans have been

documented. Given enough opportunities to cross species bar-riers, a hitherto unforeseen FV pathogenicity may reveal itself.

REFERENCES

1. Achong, B. G., and M. A. Epstein. 1983. Naturally occurring antibodies tothe human syncytial virus in West Africa. J. Med. Virol. 11:53–57.

2. Achong, B. G., and M. A. Epstein. 1978. Preliminary seroepidemiologicalstudies on the human syncytial virus. J. Gen. Virol. 40:175–181.

3. Achong, B. G., P. W. A. Mansell, M. A. Epstein, and P. Clifford. 1971. Anunusual virus in cultures from a human nasopharyngeal carcinoma. J. Natl.Cancer Inst. 46:299–307.

4. Agrba, V. Z., L. V. Kokosha, L. A. Iakovleva, V. V. Timanovskaia, and G. N.Chuvirov. 1978. Foamy viruses in baboons and macaques. Vopr. Virusol.2:179–187. (In Russian.)

5. Aguzzi, A. 1993. The foamy virus family: molecular biology, epidemiologyand neuropathology. Biochim. Biophys. Acta 1155:1–24.

6. Aguzzi, A., K. Bothe, I. Anhauser, I. Horak, A. Rethwilm, and E. F. Wagner.1992. Expression of human foamy virus is differentially regulated duringdevelopment in transgenic mice. New Biol. 4:225–237.

7. Aguzzi, A., S. Marino, R. Tschopp, and A. Rethwilm. 1996. Regulation ofexpression and pathogenic potential of human foamy virus in vitro and intransgenic mice. Curr. Top. Microbiol. Immunol. 206:243–273.

8. Aguzzi, A., E. F. Wagner, K. O. Netzer, K. Bothe, I. Anhauser, and A.Rethwilm. 1993. Human foamy virus proteins accumulate in neurons andinduce multinucleated giant cells in the brain of transgenic mice. Am. J.Pathol. 142:1061–1071. (Erratum 143:648.)

9. Ali, M., G. P. Taylor, R. J. Pitman, D. Parker, A. Rethwilm, R. Cheingsong-Popov, J. N. Weber, P. D. Bieniasz, J. Bradley, and M. O. McClure. 1996.No evidence of antibody to human foamy virus in widespread humanpopulations. AIDS Res. Hum. Retroviruses. 12:1473–1483.

10. Reference deleted.11. Allan, J. S. 1998. Cross-species infection: no news is good news? [letter;

comment]. Nat Med. 4:644–645.12. Allan, J. S., S. R. Broussard, M. G. Michaels, T. E. Starzl, K. L. Leighton,

E. M. Whitehead, A. G. Comuzzie, R. E. Lanford, M. M. Leland, W. M.Switzer, and W. Heneine. 1998. Amplification of simian retroviral se-quences from human recipients of baboon liver transplants. AIDS. Res.Hum. Retroviruses 14:821–824.

13. Anonymous. 1997. Nonhuman primate spumavirus infections among per-sons with occupational exposure—United States, 1996. Morb. Mortal.Wkly. Rep. 46:129–131.

14. Baldwin, D. N., and M. L. Linial. 1998. The roles of Pol and Env in theassembly pathway of human foamy virus. J. Virol. 72:3658–3665.

15. Bieniasz, P. D., A. Rethwilm, R. Pitman, M. D. Daniel, I. Chrystie, andM. O. McClure. 1995. A comparative study of higher primate foamy viruses,including a new virus from a gorilla. Virology 207:217–228.

16. Bock, M., M. Heinkelein, D. Lindemann, and A. Rethwilm. 1998. Cellsexpressing the human foamy virus (HFV) accessory bet protein are resistantto productive HFV superinfection. Virology 250:194–204.

17. Bothe, K., A. Aguzzi, H. Lassmann, A. Rethwilm, and I. Horak. 1991.Progressive encephalopathy and myopathy in transgenic mice expressinghuman foamy virus genes. Science 253:555–557.

18. Broussard, S. R., A. G. Comuzzie, K. L. Leighton, M. M. Leland, E. M.Whitehead, and J. S. Allan. 1997. Characterization of new simian foamyviruses from African nonhuman primates. Virology 237:349–359.

19. Brown, P., M. C. Moreau-Dubois, and D. C. Gajdusek. 1982. Persistentasymptomatic infection of the laboratory mouse by simian foamy virus type6: a new model of retrovirus latency. Arch. Virol. 71:229–234.

20. Brown, P., G. Nemo, and D. C. Gajdusek. 1978. Human foamy virus: furthercharacterization, seroepidemiology, and relationship to chimpanzee foamyviruses. J. Infect. Dis. 137:421–427.

21. Callahan, M. E., W. M. Switzer, A. L. Matthews, B. D. Roberts, W. Heneine,T. M. Folks, and P. A. Sandstrom. 1999. Persistent zoonotic infection of ahuman with simian foamy virus in the absence of an intact orf-2 accessorygene. J. Virol. 73:9619–9624.

22. Cameron, K. R., S. M. Birchall, and M. A. Moses. 1978. Isolation of foamyvirus from patient with dialysis encephalopathy. Lancet ii:796.

23. Campbell, M., L. Renshaw-Gegg, R. Renne, and P. A. Luciw. 1994. Char-acterization of the internal promoter of simian foamy viruses. J. Virol.68:4811–4820.

24. Cordonnier, A., J. F. Casella, and T. Heidmann. 1995. Isolation of novelhuman endogenous retrovirus-like elements with foamy virus-related polsequence. J. Virol. 69:5890–5897.

25. Daniels, M. J., M. C. Golder, O. Jarrett, and D. W. MacDonald. 1999.Feline viruses in wildcats from Scotland. J. Wildl. Dis. 35:121–124.

26. Debons-Guillemin, M. C., J. Valla, J. Gazeau, J. Wybier-Franqui, M. L.Giron, M. E. Toubert, M. Canivet, and J. Peries. 1992. No evidence ofspumaretrovirus infection markers in 19 cases of De Quervain’s thyroiditis.AIDS Res. Hum. Retroviruses 8:1547.

27. Enders, J., and T. Peebles. 1954. Propagation in tissue cultures of cyto-



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

pathogenic agents form patients with measles. Proc. Soc. Biol. Med. 86:277–287.

28. Epstein, M. A., B. G. Achong, and G. Ball. 1974. Further observations on ahuman syncytial virus from a nasopharyngeal carcinoma. J. Natl. CancerInst. 53:681–688.

29. Erlwein, O., P. D. Bieniasz, and M. O. McClure. 1998. Sequences in pol arerequired for transfer of human foamy virus-based vectors. J. Virol. 72:5510–5516.

30. Falcone, V., J. Leupold, J. Clotten, E. Urbanyi, O. Herchenroder, W. Spatz,B. Volk, N. Bohm, A. Toniolo, D. Neumann-Haefelin, and M. Schweizer.1999. Sites of simian foamy virus persistence in naturally infected Africangreen monkeys: latent provirus is ubiquitous, whereas viral replication isrestricted to the oral mucosa. Virology 257:7–14.

31. Fischer, N., M. Heinkelein, D. Lindemann, J. Enssle, C. Baum, E. Werder,H. Zentgraf, J. G. Muller, and A. Rethwilm. 1998. Foamy virus particleformation. J. Virol. 72:1610–1615.

32. Flanagan, M. 1992. Isolation of a spumavirus from a sheep. Aust. Vet. J.69:112–113.

33. Gao, F., E. Bailes, D. L. Robertson, Y. Chen, C. M. Rodenburg, S. F.Michael, L. B. Cummins, L. O. Arthur, M. Peeters, G. M. Shaw, P. M.Sharp, and B. H. Hahn. 1999. Origin of HIV-1 in the chimpanzee Pantroglodytes troglodytes. Nature 397:436–441.

34. Gao, F., L. Yue, A. T. White, P. G. Pappas, J. Barchue, A. P. Hanson, B. M.Greene, P. M. Sharp, G. M. Shaw, and B. H. Hahn. 1992. Human infectionby genetically diverse SIVSM-related HIV-2 in west Africa. Nature 358:495–499.

35. Glaus, T., R. Hofmann-Lehmann, C. Greene, B. Glaus, C. Wolfensberger,and H. Lutz. 1997. Seroprevalence of Bartonella henselae infection andcorrelation with disease status in cats in Switzerland. J. Clin. Microbiol.35:2883–2885.

36. Goepfert, P. A., G. Ritter, Jr., X. Peng, A. A. Gbakima, Y. Zhang, and M. J.Mulligan. 1996. Analysis of west African hunters for foamy virus infections.AIDS Res. Hum. Retroviruses 12:1725–1730.

37. Goepfert, P. A., K. Shaw, G. Wang, A. Bansal, B. H. Edwards, and M. J.Mulligan. 1999. An endoplasmic reticulum retrieval signal partitions hu-man foamy virus maturation to intracytoplasmic membranes. J. Virol. 73:7210–7217.

38. Goepfert, P. A., K. L. Shaw, G. Ritter, Jr., and M. J. Mulligan. 1997. Asorting motif localizes the foamy virus glycoprotein to the endoplasmicreticulum. J. Virol. 71:778–784.

39. Goepfert, P. A., G. Wang, and M. J. Mulligan. 1995. Identification of an ERretrieval signal in retroviral glycoprotein. Cell. 82:543–544.

40. Gow, J. W., K. Simpson, A. Schliephake, W. M. Behan, L. J. Morrison, H.Cavanagh, A. Rethwilm, and P. O. Behan. 1992. Search for retrovirus in thechronic fatigue syndrome. J. Clin. Pathol. 45:1058–1061.

41. Heberling, R. L., and S. S. Kalter. 1975. Isolation of foamy viruses frombaboon (Papio cynocephalus) tissues. Am. J. Epidemiol. 102:25–29.

42. Heinkelein, M., M. Schmidt, N. Fischer, A. Moebes, D. Lindemann, J.Enssle, and A. Rethwilm. 1998. Characterization of a cis-acting sequence inthe pol region required to transfer human foamy virus vectors. J. Virol.72:6307–6314.

43. Heneine, W., V. C. Musey, S. D. Sinha, A. Landay, G. Northrup, R. Khab-baz, and J. E. Kaplan. 1995. Absence of evidence for human spumaretro-virus sequences in patients with Graves’ disease. J. Acquir. Immune Defic.Syndr. Hum. Retrovirol. 9:99–101.

44. Heneine, W., W. M. Switzer, P. Sandstrom, J. Brown, S. Vedapuri, C. A.Schable, A. S. Khan, N. W. Lerche, M. Schweizer, D. Neumann-Haefelin,L. E. Chapman, and T. M. Folks. 1998. Identification of a human popula-tion infected with simian foamy viruses. Nat. Med. 4:403–407.

45. Reference deleted.46. Herchenroder, O., R. Renne, D. Loncar, E. K. Cobb, K. K. Murthy, J.

Schneider, A. Mergia, and P. A. Luciw. 1994. Isolation, cloning, and se-quencing of simian foamy viruses from chimpanzees (SFVcpz): high ho-mology to human foamy virus (HFV). Virology 201:187–199.

47. Hill, C. L., P. D. Bieniasz, and M. O. McClure. 1999. Properties of humanfoamy virus relevant to its development as a vector for gene therapy. J. Gen.Virol. 80:2003–2009.

48. Hirata, R. K., A. D. Miller, R. G. Andrews, and D. W. Russell. 1996.Transduction of hematopoietic cells by foamy virus vectors. Blood 88:3654–3661.

49. Hooks, J. J., and B. Detrick-Hooks. 1979. Simian foamy virus-inducedimmunosuppression in rabbits. J. Gen. Virol. 44:383–390.

50. Hooks, J. J., and C. Gibbs, Jr. 1975. The foamy viruses. Bacteriol. Rev.39:169–185.

51. Hooks, J. J., C. Gibbs, Jr., S. Chou, R. Howk, M. Lewis, and D. C. Gaj-dusek. 1973. Isolation of a new simian foamy virus from a spider monkeybrain culture. Infect. Immun. 8:804–813.

52. Hooks, J. J., C. Gibbs, Jr., E. C. Cutchins, N. G. Rogers, P. Lampert, andD. C. Gajdusek. 1972. Characterization and distribution of two new foamyviruses isolated from chimpanzees. Arch. Gesamte Virusforsch. 38:38–55.

53. Hruska, J. F., and K. K. Takemoto. 1975. Biochemical properties of a

hamster syncytium-forming (“foamy”) virus. J. Natl. Cancer Inst. 54:601–605.

54. Jacobs, R. M., F. L. Pollari, W. B. McNab, and B. Jefferson. 1995. Aserological survey of bovine syncytial virus in Ontario: associations withbovine leukemia and immunodeficiency-like viruses, production records,and management practices. Can. J. Vet. Res. 59:271–278.

55. Johnson, R. H., J. de la Rosa, I. Abher, I. G. Kertayadnya, K. W. Entwistle,G. Fordyce, and R. G. Holroyd. 1988. Epidemiological studies of bovinespumavirus. Vet. Microbiol. 16:25–33.

56. Johnston, P. 1961. A second immunologic type of simian foamy virus:monkey throat infections and unmasking by both types. J. Infect. Dis.109:1–9.

57. Johnston, P. B. 1974. Studies on simian foamy viruses and syncytium-forming viruses of lower animals. Lab. Anim. Sci. 24:159–166.

58. Johnston, P. B. 1971. Taxonomic features of seven serotypes of simian andape foamy viruses. Infect. Immun. 3:793–799.

59. Kennedy-Stoskopf, S., M. K. Stoskopf, M. A. Eckhaus, and J. D. Strand-berg. 1986. Isolation of a retrovirus and a herpesvirus from a captiveCalifornia sea lion. J. Wildl. Dis. 22:156–164.

60. Kertayadnya, I. G., R. H. Johnson, I. Abher, and G. W. Burgess. 1988.Detection of immunological tolerance to bovine spumavirus (BSV) withevidence for salivary excretion and spread of BSV from the tolerant animal.Vet. Microbiol. 16:35–39.

61. Lagaye, S., P. Vexiau, V. Morozov, V. Guenebaut-Claudet, J. Tobaly-Tapi-ero, M. Canivet, G. Cathelineau, J. Peries, and R. Emanoil-Ravier. 1992.Human spumaretrovirus-related sequences in the DNA of leukocytes frompatients with Graves disease. Proc. Natl. Acad. Sci. USA 89:10070–10074.

62. Lee, H., S. Kim, M. Kang, W. Kim, and B. Cho. 1998. Prevalence of humanfoamy virus-related sequences in the Korean population. J. Biomed. Sci.5:267–273.

63. Linial, M., L. 1999. Foamy viruses are unconventional retroviruses. J. Virol.73:1747–1755.

64. Liu, W. T., K. P. Kao, Y. C. Liu, and K. S. Chang. 1996. Human foamy virusgenome in the thymus of myasthenia gravis patients. Chung-Hua Min KuoWei Sheng Wu Chi Mien I Hsuech Tsa Chih 29:162–165.

65. Lochelt, M., M. Aboud, and R. M. Flugel. 1993. Increase in the basaltranscriptional activity of the human foamy virus internal promoter by thehomologous long terminal repeat promoter in cis. Nucleic Acids Res. 21:4226–4230.

66. Lochelt, M., R. M. Flugel, and M. Aboud. 1994. The human foamy virusinternal promoter directs the expression of the functional Bel 1 transacti-vator and Bet protein early after infection. J. Virol. 68:638–645.

67. Lochelt, M., W. Muranyi, and R. M. Flugel. 1993. Human foamy virusgenome possesses an internal, Bel-1-dependent and functional promoter.Proc. Natl. Acad. Sci. USA 90:7317–7321.

68. Lochelt, M., H. Zentgraf, and R. M. Flugel. 1991. Construction of aninfectious DNA clone of the full-length human spumaretrovirus genomeand mutagenesis of the bel 1 gene. Virology 184:43–54.

69. Loh, P. C., F. Matsuura, and C. Mizumoto. 1980. Seroepidemiology ofhuman syncytial virus: antibody prevalence in the Pacific. Intervirology13:87–90.

70. Lycke, J., B. Svennerholm, A. Svenningsson, W. Muranyi, R. M. Flugel, andO. Andersen. 1994. Human spumaretrovirus antibody reactivity in multiplesclerosis. J. Neurol. 241:204–209.

71. Mahnke, C., P. Kashaiya, J. Rossler, H. Bannert, A. Levin, W. A. Blattner,M. Dietrich, J. Luande, M. Lochelt, A. E. Friedman-Kien, et al. 1992.Human spumavirus antibodies in sera from African patients. Arch. Virol.123:243–253.

72. Malmquist, W. A., M. J. Van der Maaten, and A. D. Boothe. 1969. Isolation,immunodiffusion, immunofluorescence, and electron microscopy of a syn-cytial virus of lymphosarcomatous and apparently normal cattle. CancerRes. 29:188–200.

73. Marczynska, B., C. J. Jones, and L. G. Wolfe. 1981. Syncytium-formingvirus of common marmosets (Callithrix jacchus jacchus). Infect. Immun.31:1261–1269.

74. McClure, M. O., P. D. Bieniasz, T. F. Schulz, I. L. Chrystie, G. Simpson, A.Aguzzi, J. G. Hoad, A. Cunningham, J. Kirkwood, and R. A. Weiss. 1994.Isolation of a new foamy retrovirus from orangutans. J. Virol. 68:7124–7130.

75. Mergia, A. 1994. Simian foamy virus type 1 contains a second promoterlocated at the 3' end of the env gene. Virology 199:219–222.

76. Mergia, A., N. J. Leung, and J. Blackwell. 1996. Cell tropism of the simianfoamy virus type 1 (SFV-1). J. Med. Primatol. 25:2–7.

77. Mergia, A., K. E. Shaw, E. Pratt-Lowe, P. A. Barry, and P. A. Luciw. 1991.Identification of the simian foamy virus transcriptional transactivator gene(taf). J. Virol. 65:2903–2909.

78. Mikovits, J. A., P. M. Hoffman, A. Rethwilm, and F. W. Ruscetti. 1996. Invitro infection of primary and retrovirus-infected human leukocytes byhuman foamy virus. J. Virol. 70:2774–2780.

79. Moebes, A., J. Enssle, P. D. Bieniasz, M. Heinkelein, D. Lindemann, M.Bock, M. O. McClure, and A. Rethwilm. 1997. Human foamy virus reverse



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

transcription that occurs late in the viral replication cycle. J. Virol. 71:7305–7311.

80. Muller, H. K., G. Ball, M. A. Epstein, B. G. Achong, G. Lenoir, and A.Levin. 1980. The prevalence of naturally occurring antibodies to humansyncytial virus in East African populations. J. Gen. Virol. 47:399–406.

81. Myers, G., K. MacInnes, and B. Korber. 1992. The emergence of simian/human immunodeficiency viruses. AIDS Res. Hum. Retroviruses 8:373–386.

82. Nemo, G. J., P. W. Brown, C. Gibbs, Jr., and D. C. Gajdusek. 1978.Antigenic relationship of human foamy virus to the simian foamy viruses.Infect. Immun. 20:69–72.

83. Pietschmann, T., M. Heinkelein, M. Heldmann, H. Zentgraf, A. Rethwilm,and D. Lindemann. 1999. Foamy virus capsids require the cognate envelopeprotein for particle export. J. Virol. 73:2613–2621.

84. Pyykko, I., M. Vesanen, K. Asikainen, M. Koskiniemi, L. Airaksinen, and A.Vaheri. 1994. Human spumaretrovirus in the etiology of sudden hearingloss. Acta Otolaryngol. 114:224.

85. Rethwilm, A., G. Baunach, K. O. Netzer, B. Maurer, B. Borisch, and V. terMeulen. 1990. Infectious DNA of the human spumaretrovirus. NucleicAcids Res. 18:733–738.

86. Rethwilm, A., G. Darai, A. Rosen, B. Maurer, and R. M. Flugel. 1987.Molecular cloning of the genome of human spumaretrovirus. Gene 59:19–28.

87. Rethwilm, A., O. Erlwein, G. Baunach, B. Maurer, and V. ter Meulen. 1991.The transcriptional transactivator of human foamy virus maps to the bel 1genomic region. Proc. Natl. Acad. Sci. USA 88:941–945.

88. Riggs, J. L., L. S. Oshire, D. O. N. Taylor, and E. H. Lennette. 1969.Syncytium-forming agents isolated from domestic cats. Nature 222:1190.

89. Rogers, N., M. Basnight, C. H. Gibbs, and D. C. Gajdusek. 1967. Latentviruses in chimpanzees with experimental kuru. Nature 216:446–449.

90. Rosener, M., H. Hahn, M. Kranz, J. Heeney, and A. Rethwilm. 1996.Absence of serological evidence for foamy virus infection in patients withamyotrophic lateral sclerosis. J. Med. Virol. 48:222–226.

91. Rustigian, R., P. Johnston, and H. Rejhart. 1955. Infection of monkeykidney tissue cultures with virus-like agents. Proc. Soc. Exp. Biol. Med.88:8–16.

92. Saib, A., M. Canivet, M. L. Giron, F. Bolgert, J. Valla, S. Lagaye, J. Peries,and H. de The. 1994. Human foamy virus infection in myasthenia gravis.Lancet 343:666.

93. Saib, A., M. H. Koken, P. van der Spek, J. Peries, and H. de The. 1995.Involvement of a spliced and defective human foamy virus in the establish-ment of chronic infection. J. Virol. 69:5261–5268.

94. Saib, A., M. Neves, M. L. Giron, M. C. Guillemin, J. Valla, J. Peries, andM. Canivet. 1997. Long-term persistent infection of domestic rabbits by thehuman foamy virus. Virology 228:263–268.

95. Saib, A., J. Peries, and H. de The. 1993. A defective human foamy provirusgenerated by pregenome splicing. EMBO J. 12:4439–4444.

96. Santillana-Hayat, M., F. Rozain, P. Bittoun, C. Chopin-Robert, J. Lasneret,J. Peries, and M. Canivet. 1993. Transient immunosuppressive effect in-duced in rabbits and mice by the human spumaretrovirus prototype HFV(human foamy virus). Res. Virol. 144:389–396.

97. Schenk, T., J. Enssle, N. Fischer, and A. Rethwilm. 1999. Replication of afoamy virus mutant with a constitutively active U3 promoter and deletedaccessory genes. J. Gen. Virol. 80:1591–1598.

98. Schmidt, M., S. Niewiesk, J. Heeney, A. Aguzzi, and A. Rethwilm. 1997.Mouse model to study the replication of primate foamy viruses. J. Gen.Virol. 78:1929–1933.

99. Schmidt, M., and A. Rethwilm. 1995. Replicating foamy virus-based vectorsdirecting high level expression of foreign genes. Virology 210:167–178.

100. Schweizer, M., V. Falcone, J. Gange, R. Turek, and D. Neumann-Haefelin.1997. Simian foamy virus isolated from an accidentally infected humanindividual. J. Virol. 71:4821–4824.

101. Schweizer, M., and D. Neumann-Haefelin. 1995. Phylogenetic analysis ofprimate foamy viruses by comparison of pol sequences. Virology 207:577–582.

102. Schweizer, M., H. Schleer, M. Pietrek, J. Liegibel, V. Falcone, and D.Neumann-Haefelin. 1999. Genetic stability of foamy viruses: long-termstudy in an African green monkey population. J. Virol. 73:9256–9265.

103. Schweizer, M., R. Turek, H. Hahn, A. Schliephake, K. O. Netzer, G. Eder,M. Reinhardt, A. Rethwilm, and D. Neumann-Haefelin. 1995. Markers offoamy virus infections in monkeys, apes, and accidentally infected humans:appropriate testing fails to confirm suspected foamy virus prevalence inhumans. AIDS Res. Hum. Retroviruses 11:161–170.

104. Schweizer, M., R. Turek, M. Reinhardt, and D. Neumann-Haefelin. 1994.

Absence of foamy virus DNA in Graves’ disease. AIDS Res. Hum. Retro-viruses 10:601–605.

105. Stancek, D., F. Ciampor, V. Mucha, P. Hnilica, and M. Stancekova. 1976.Morphological, cytological and biological observations on viruses isolatedfrom patients with subacute thyroiditis de Quervain. Acta Virol. 20:183–188.

106. Stancek, D., and M. Gressnerova. 1974. A viral agent isolated from apatient with subacute de Quervain type thyroiditis. Acta Virol. 18:365.

107. Stancek, D., M. Stancekova-Gressnerova, M. Janotka, P. Hnilica, and D.Oravec. 1975. Isolation and some serological and epidemiological data onthe viruses recovered from patients with subacute thyroiditis de Quervain.Med. Microbiol. Immunol. (Berlin) 161:133–144.

108. Starzl, T. E., J. Fung, A. Tzakis, S. Todo, A. J. Demetris, I. R. Marino, H.Doyle, A. Zeevi, V. Warty, M. Michaels, et al. 1993. Baboon-to-human livertransplantation. Lancet 341:65–71.

109. Stiles, G. E. 1968. Serologic screening of rhesus and grivet monkeys forSV40 and the foamy viruses. Proc. Soc. Exp. Biol. Med. 127:225–230.

110. Stiles, G. E., J. L. Bittle, and U. J. Babasso. 1964. Comparison of simianfoamy virus strains including a new serological type. Nature 201:1350.

111. Svenningsson, A., J. Lycke, B. Svennerholm, S. Gronowitz, and O.Andersen. 1992. No evidence for spumavirus or oncovirus infection inrelapsing-remitting multiple sclerosis. Ann. Neurol. 32:711–714.

112. Swack, N. S., and G. D. Hsiung. 1975. Pathogenesis of simian foamy virusinfection in natural and experimental hosts. Infect. Immun. 12:470–474.

113. Tamura, N., and S. Kira. 1995. Human foamy virus and familial Mediter-ranean fever in Japan. JAMA 274:1509.

114. Tobaly-Tapiero, J., P. Bittoun, M. Neves, M. C. Guillemin, C. H. Lecellier,F. Puvion-Dutilleul, B. Gicquel, S. Zientara, M. L. Giron, H. de The, and A.Saib. 2000. Isolation and characterization of an equine foamy virus. J. Virol.74:4064–4073.

115. Trobridge, G. D., and D. W. Russell. 1998. Helper-free foamy virus vectors.Hum. Gene Ther. 9:2517–2525.

116. Tschopp, R. R., S. Brandner, S. Marino, K. Bothe, I. Horak, A. Rethwilm,and A. Aguzzi. 1996. Analysis of the determinants of neurotropism andneurotoxicity of HFV in transgenic mice. Virology 216:338–346.

117. von Laer, D., D. Neumann-Haefelin, J. L. Heeney, and M. Schweizer. 1996.Lymphocytes are the major reservoir for foamy viruses in peripheral blood.Virology 221:240–244.

118. Weiss, R. A. 1988. Foamy retroviruses: a virus in search of a disease. Nature333:497–498.

119. Werner, J., and H. Gelderblom. 1979. Isolation of foamy virus from patientswith de Quervain thyroiditis. Lancet ii:258–259.

120. Westarp, M. E., P. Bartmann, R. Hoff-Jorgensen, J. Clausen, H. Rasmus-sen, and H. H. Kornhuber. 1993. Amyotrophic lateral sclerosis—indicationsof increased antiretroviral seroreactivity without obvious epidemiology.Nervenarzt 64:384–389. (In German.)

121. Westarp, M. E., D. Fuchs, P. Bartmann, R. Hoff-Jorgensen, J. Clausen, H.Wachter, and H. H. Kornhuber. 1993. Amyotrophic lateral sclerosis anenigmatic disease with B-cellular and anti-retroviral immune responses.Eur. J. Med. 2:327–332.

122. Wick, G., B. Grubeck-Loebenstein, K. Trieb, G. Kalischnig, and A. Aguzzi.1992. Human foamy virus antigens in thyroid tissue of Graves’ diseasepatients. Int. Arch. Allergy Immunol. 99:153–156.

123. Wick, G., K. Trieb, A. Aguzzi, H. Recheis, H. Anderl, and B. Grubeck-Loebenstein. 1993. Possible role of human foamy virus in Graves’ disease.Intervirology 35:101–107.

124. Winkler, I. G., R. M. Flugel, M. Lochelt, and R. L. Flower. 1998. Detectionand molecular characterisation of feline foamy virus serotypes in naturallyinfected cats. Virology 247:144–1451.

125. Winkler, I. G., M. Lochelt, and R. L. Flower. 1999. Epidemiology of felinefoamy virus and feline immunodeficiency virus infections in domestic andferal cats: a seroepidemiological study. J. Clin. Microbiol. 37:2848–2851.

126. Wu, M., and A. Mergia. 1999. Packaging cell lines for simian foamy virustype 1 vectors. J. Virol. 73:4498–4501.

127. Wybier-Franqui, J., J. Tobaly-Tapiero, A. Coronel, M. L. Giron, C. Chopin-Robert, J. Peries, and R. Emanoil-Ravier. 1995. Human foamy virus DNAforms and expression in persistently infected Dami megakaryocytic cells.AIDS Res. Hum. Retroviruses 11:829–836.

128. Yanagawa, T., K. Ito, E. L. Kaplan, N. Ishikawa, and L. J. DeGroot. 1995.Absence of association between human spumaretrovirus and Graves’ dis-ease. Thyroid 5:379–382.

129. Yu, S. F., J. Stone, and M. L. Linial. 1996. Productive persistent infectionof hematopoietic cells by human foamy virus. J. Virol. 70:1250–1254.

130. Yu, S. F., M. D. Sullivan, and M. L. Linial. 1999. Evidence that the humanfoamy virus genome is DNA. J. Virol. 73:1565–1572.



http://cmr.asm

.org/D

ownloaded from

http://cmr.asm.org/

historical perspective of foamy virus epidemiology and ... · foamy viruses (fv), or spumaviruses,...

Documents