Simian Foamy Viruses (SFV)

Arifa S. Khan, Ph.D.

DVP, OVRR, CBER, FDA

BPAC, December 13, 2001

FV ClassificationFV Classification Family: Retroviridae Genus: Spumavirus Single-stranded RNA genome (12-13 kb)Single-stranded RNA genome (12-13 kb) tRNAtRNAlys1,2lys1,2 primer for minus-strand synthesis primer for minus-strand synthesis Integration is a critical event in the virus life cycleIntegration is a critical event in the virus life cycle Encode proteases and integrases Encode proteases and integrases

• Complex genome: Complex genome: gag, pol, envgag, pol, env + several ORFs + several ORFs

• Temporal regulation of transcriptionTemporal regulation of transcription

• Highly cytopathic with broad species-, tissue-, and cell-tropismHighly cytopathic with broad species-, tissue-, and cell-tropism

• Highly cell-associatedHighly cell-associated

• No evidence of pathogenicity in either natural or accidentally No evidence of pathogenicity in either natural or accidentally infected hostsinfected hosts

FV ClassificationFV Classification

Family: Family: HepadnaviridaeHepadnaviridae• Replication mechanism similar to complex DNA viruses: Replication mechanism similar to complex DNA viruses:

multiple promoters (LTR, IP)multiple promoters (LTR, IP)

• Infectious particles have linear, DNA genomesInfectious particles have linear, DNA genomes

• Late reverse transcription Late reverse transcription

• Mature virions composed of two large Gag proteinsMature virions composed of two large Gag proteins

• Viral budding requires both Gag and EnvViral budding requires both Gag and Env

• Majority of virus buds through the ER. Most virus is Majority of virus buds through the ER. Most virus is

intracellular.intracellular.

• Peristently infected cells contain large amounts of DNA Peristently infected cells contain large amounts of DNA

(intracellular cycling pathway)(intracellular cycling pathway)

LTRprt-pol

envtas

orf-2

LTR

gag

SFV GENOME STRUCTURE

FV Replication Cycle

rtrt

ERER buddingbudding

CYTOPLASMCYTOPLASM NUCLEUSNUCLEUS

rtrt

rtrt

rtrt

integinteg

uncoatuncoat

vDNAvDNA

vRNAvRNA

vCoresvCores??

FV: Species Distribution

Species Virus DesignationSpecies Virus Designation

Simian Simian foamy virus (SFV) Simian Simian foamy virus (SFV)

Bovine Bovine syncytium-forming virus (BSFV; BFV)Bovine Bovine syncytium-forming virus (BSFV; BFV)

Feline Feline syncytium-forming virus (FeSFV; FFV)Feline Feline syncytium-forming virus (FeSFV; FFV)

Murine Hamster syncytium-forming virus (HaSFV)Murine Hamster syncytium-forming virus (HaSFV)

Otariidine Sea lion foamy virusOtariidine Sea lion foamy virus

Ovine Sheep foamy virusOvine Sheep foamy virus

Equine Horse foamy virus (EFV)Equine Horse foamy virus (EFV)

Human Human foamy virus (HFV; SFVcpz[hu]; Human Human foamy virus (HFV; SFVcpz[hu];

Acquired by cross-infection from a chimpanzeeAcquired by cross-infection from a chimpanzee)

SFV Prevalence in Primates SpeciesSFV Prevalence in Primates Species

• Prosimian Prosimian

GalagoGalago

• New World Primates New World Primates

Squirrel, Spider, Capuchin, MarmosetSquirrel, Spider, Capuchin, Marmoset

• Old World PrimatesOld World Primates

Macaques [Macaques [Rhesus, Pigtailed, Cynomolgus, Rhesus, Pigtailed, Cynomolgus,

Formosan Rock macaque, BonnetFormosan Rock macaque, Bonnet], ],

African green monkey; Mangabey; BaboonAfrican green monkey; Mangabey; Baboon

• Apes Apes

Chimpanzee, Orangutan, GorillaChimpanzee, Orangutan, Gorilla

SFV Biology: Host Range and Cell TropismSFV Biology: Host Range and Cell Tropism

Exceptionally broad host rangeExceptionally broad host range

Non-Primate Cell Type Tissue OriginNon-Primate Cell Type Tissue Origin

SpeciesSpecies

Chicken, QuailChicken, Quail Fibroblast Embyro Fibroblast Embyro

Mouse Mouse Fibroblast Embryo, Tail Fibroblast Embryo, Tail

Dog Dog Fibroblast Thymus Fibroblast Thymus

Cat Cat Fibroblast Kidney Fibroblast Kidney

SFV Biology: Host Range and Cell TropismSFV Biology: Host Range and Cell Tropism

Primate Cell Type Tissue OriginPrimate Cell Type Tissue Origin

SpeciesSpecies

Monkey Monkey Fibroblast Lung, KidneyFibroblast Lung, Kidney

Epithelial KidneyEpithelial Kidney

Macrophage LungMacrophage Lung

HumanHuman Fibroblast LungFibroblast Lung

Epithelial Lung, MuscleEpithelial Lung, Muscle

Lymphoid T cells, B cellsLymphoid T cells, B cells

MacrophageMacrophage

NeuralNeural

SFV Biology: SFV Biology: In VitroIn Vitro Replication Replication

SFV can replicate in all species SFV can replicate in all species Replication efficiency- Cell type dependent ((Mergia et al.,Mergia et al., J. Med. Primatol. 1996J. Med. Primatol. 1996) )

Fibroblasts and Epithelial cells > Lymphoid and Fibroblasts and Epithelial cells > Lymphoid and

Macrophage cellsMacrophage cells Virus type dependent ((Khan et al., submittedKhan et al., submitted))

Prototype SFV-1 and SFV-2 > Naturally-occurring IsolatesPrototype SFV-1 and SFV-2 > Naturally-occurring Isolates Virus isolate dependent ((Khan et al., submittedKhan et al., submitted))

SFV-1 > SFV-2 > Naturally-occurring IsolatesSFV-1 > SFV-2 > Naturally-occurring Isolates

Latent Infection of A549 Human Tumor Cells Latent Infection of A549 Human Tumor Cells with Naturally Occurring SFV Isolateswith 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 Infection Productive InfectionProductive Infection: Most cell types especially fibroblastsMost cell types especially fibroblasts

- Variable amount of extracellular virus production Variable amount of extracellular virus production

(depending upon the species, tissue origin and (depending upon the species, tissue origin and

cell type- cell type- Mus dunniMus dunni cells most sensitive) cells most sensitive)

- Cytopathic Effect- Lysis, Apoptosis- Cytopathic Effect- Lysis, Apoptosis Chronic InfectionChronic Infection: Transformed cell lines of myeloid, Transformed cell lines of myeloid,

erythroid, and lymphoid origin erythroid, and lymphoid origin

- Low level virus production- Low level virus production

- No Cytopathic Effect- No Cytopathic Effect Latent InfectionLatent Infection:Selected casesSelected cases

- No virus production- No virus production

- Virus induction/reactivation- Virus induction/reactivation

SFV Natural infection in Non-human PrimatesSFV Natural infection in Non-human Primates

SFV is widespread in all non-human primate speciesSFV 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 SFV Experimental Infection in AnimalsAnimals

Immunocompetent rabbits and mice Immunocompetent rabbits and mice [SFVmac; SFVcpz; SFVcpz(hu)] [SFVmac; SFVcpz; SFVcpz(hu)]

Persistent infectionPersistent infection

Transient immunosuppressive effectTransient immunosuppressive effect

No signs of any disease; no pathologyNo signs of any disease; no pathology

In general, SFV infection in small animals was In general, SFV infection in small animals was similar to naturally occurring infection in non-similar to naturally occurring infection in non-human primates. human primates.

SFV Experimental Infection in Animals

Transgenic Mice [SFVcpz(hu)]Transgenic Mice [SFVcpz(hu)]• Transgene expression in forebrain and Transgene expression in forebrain and

cerbellum resulted in pathology in cerbellum resulted in pathology in

tissues of the central nervous system tissues of the central nervous system

and striated. Probably due to ORFs and striated. Probably due to ORFs

(tas, bet). (tas, bet). • Pathology enhanced in the presence of Pathology enhanced in the presence of

structural genes. structural genes. • FV replication not demonstrated.FV replication not demonstrated.

SFV “Accidental” Infection in Occupationally Exposed Humans

• SFV 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 PathogenesisSFV Pathogenesis““A Virus in Search of a Disease”A Virus in Search of a Disease”

[Weiss, R.A., 1988, Nature (London) 333, 497-498]

• Tenuous association with various diseases in humans: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 In most studies, use of multiple detection assay failed to confirm the initial disease associationconfirm 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 Pathogenesis

““A Virus in Search of a Disease” A 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 Summary• SFV transmission is high in non human primates SFV transmission is high in non human primates

probably due to saliva. No disease.probably due to saliva. No disease.

• SFV can infect humans due to accidental exposure SFV can infect humans due to accidental exposure

(mostly due to bites; other?). No evidence of human- (mostly due to bites; other?). No evidence of human-

to-human transmission. No evidence of any virus-to-human transmission. No evidence of any virus-

associated disease.associated disease.

• Experimental infection of mice and rabbits Experimental infection of mice and rabbits

demonstrated by different routes: intradermal, demonstrated by different routes: intradermal,

intraperitoneal, intranasal. No disease in normal intraperitoneal, intranasal. No disease in normal

animals. Disease in transgenic mice due to proteins.animals. Disease in transgenic mice due to proteins. No evidence of FV transmission by blood due to lack of No evidence of FV transmission by blood due to lack of

relevant animal studies.relevant animal studies.