Simian Foamy Viruses (SFV)Arifa S. Khan, Ph.D.DVP, OVRR, CBER, FDABPAC, December 13, 2001

FV Classification Family: Retroviridae Genus: Spumavirus Single-stranded RNA genome (12-13 kb) tRNAlys1,2 primer for minus-strand synthesis Integration is a critical event in the virus life cycle Encode proteases and integrases

Complex genome: gag, pol, env + several ORFs Temporal regulation of transcriptionHighly cytopathic with broad species-, tissue-, and cell-tropismHighly cell-associatedNo evidence of pathogenicity in either natural or accidentally infected hosts

FV Classification Family: Hepadnaviridae Replication mechanism similar to complex DNA viruses: multiple promoters (LTR, IP) Infectious particles have linear, DNA genomes Late reverse transcription Mature virions composed of two large Gag proteins Viral budding requires both Gag and Env Majority of virus buds through the ER. Most virus is intracellular. Peristently infected cells contain large amounts of DNA (intracellular cycling pathway)

LTRprt-polenvtasorf-2LTR gag SFV GENOME STRUCTURE

FV Replication Cyclert ER buddingCYTOPLASMNUCLEUSrtrtrtinteguncoatvDNAvRNAvCores??

FV: Species DistributionSpecies Virus Designation

Simian Simian foamy virus (SFV) Bovine Bovine syncytium-forming virus (BSFV; BFV)Feline Feline syncytium-forming virus (FeSFV; FFV)Murine Hamster syncytium-forming virus (HaSFV)Otariidine Sea lion foamy virusOvine Sheep foamy virusEquine Horse foamy virus (EFV)Human Human foamy virus (HFV; SFVcpz[hu]; Acquired by cross-infection from a chimpanzee)

SFV Prevalence in Primates SpeciesProsimian GalagoNew World Primates Squirrel, Spider, Capuchin, MarmosetOld World Primates Macaques [Rhesus, Pigtailed, Cynomolgus, Formosan Rock macaque, Bonnet], African green monkey; Mangabey; Baboon Apes Chimpanzee, Orangutan, Gorilla

SFV Biology: Host Range and Cell TropismExceptionally broad host range

Non-Primate Cell Type Tissue OriginSpecies

Chicken, Quail Fibroblast Embyro

Mouse Fibroblast Embryo, Tail

Dog Fibroblast Thymus

Cat Fibroblast Kidney

SFV Biology: Host Range and Cell TropismPrimate Cell Type Tissue OriginSpecies

Monkey Fibroblast Lung, Kidney Epithelial Kidney Macrophage Lung

Human Fibroblast Lung Epithelial Lung, Muscle Lymphoid T cells, B cells Macrophage Neural

SFV Biology: In Vitro Replication SFV can replicate in all species Replication efficiency-Cell type dependent (Mergia et al., J. Med. Primatol. 1996) Fibroblasts and Epithelial cells > Lymphoid and Macrophage cellsVirus type dependent (Khan et al., submitted) Prototype SFV-1 and SFV-2 > Naturally-occurring IsolatesVirus isolate dependent (Khan et al., submitted) SFV-1 > SFV-2 > Naturally-occurring Isolates

Latent Infection of A549 Human Tumor Cells with Naturally Occurring SFV Isolates

Lack of Virus Production in SFV Infected A549 Cells using STF-PERT Assay

PCR Detection of SFV Sequences in SFV Infected A549 Cells

SFV BIOLOGY: In Vitro InfectionProductive Infection: Most cell types especially fibroblasts - Variable amount of extracellular virus production (depending upon the species, tissue origin and cell type- Mus dunni cells most sensitive) - Cytopathic Effect- Lysis, ApoptosisChronic Infection: Transformed cell lines of myeloid, erythroid, and lymphoid origin - Low level virus production - No Cytopathic Effect Latent Infection:Selected cases - No virus production - Virus induction/reactivation

SFV Natural infection in Non-human PrimatesSFV is widespread in all non-human primate species Eleven serologically distinct subtypes (SFV-1 to SFV-11) Seroprevalence is high in capitivity (93% in AGM; Schweizer et al., 1995) Higher incidence in adults than infants (about 30% seropositive by 1 year of age in a baboon breeding colony- Blewett et al., 2000) Sequences genetically stable (minimal genetic drift over 13 years in AGM study- Schweizer et al., 1999) Broad tissue distribution (viral DNA persist in all tissues in AGM- Falcone et al., 1999) Latent, peristent infection (viral RNA detected only in oral mucosa- Falcone et al., 1999)

SFV Experimental Infection in AnimalsImmunocompetent rabbits and mice [SFVmac; SFVcpz; SFVcpz(hu)] Persistent infection Transient immunosuppressive effect No signs of any disease; no pathology In general, SFV infection in small animals was similar to naturally occurring infection in non-human primates.

SFV Experimental Infection in AnimalsTransgenic Mice [SFVcpz(hu)]Transgene expression in forebrain and cerbellum resulted in pathology in tissues of the central nervous system and striated. Probably due to ORFs (tas, bet). Pathology enhanced in the presence of structural genes. FV replication not demonstrated.

SFV Accidental Infection in Occupationally Exposed HumansSFV infection in non-human primate handlers and zoo keepers has occurred due to exposure to African green monkey, chimpanzee, baboon, macaque.Pesistent virus infection (>30 years in one animal handler)Latent virus infection (no evidence of plasma viremia; virus isolated in co-culture from peripheral blood lymphocytes).No evidence of virus transmission in close contacts.No clinical signs of FV-associated disease.

SFV PathogenesisA Virus in Search of a Disease[Weiss, R.A., 1988, Nature (London) 333, 497-498]Tenuous association with various diseases in humans: Thyroiditis de Quervain, Graves disease, Multiple sclerosis, Chronic fatigue syndrome, Familial Mediterranean fever, Senorineural hearing loss, Dialysis encephalopathy, and Myasthenia gravis.In most studies, use of multiple detection assay failed to confirm the initial disease association. In Myasthenia Gravis FV detected by serological and molecular assays but no infectious virus recovered. The authors suggested further studies be done to confirm the role of FV as an etiological agent in Myasthenia Gravis.

SFV PathogenesisA Virus in Search of a Disease [Weiss, R.A. 1988 Nature (London) 333, 497-498]

No evidence of any disease in non-human primates due to naturally occurring SFV. In small animal models using prototype, laboratory-adapted viruses, no disease seen in immunocompetent rabbits or mice; disease seen in transgenic mice due to protein expression.No evidence of disease in SFV-infected humans

SFV SummarySFV transmission is high in non human primates probably due to saliva. No disease.SFV can infect humans due to accidental exposure (mostly due to bites; other?). No evidence of human- to-human transmission. No evidence of any virus- associated disease.Experimental infection of mice and rabbits demonstrated by different routes: intradermal, intraperitoneal, intranasal. No disease in normal animals. Disease in transgenic mice due to proteins.No evidence of FV transmission by blood due to lack of relevant animal studies.