Simian Foamy Viruses (SFV)

Arifa S. Khan, Ph.D. DVP, OVRR, CBER, FDA BPAC, 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 transcription Highly cytopathic with broad species-, tissue-, and cell-tropism Highly cell-associated No 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)

SFV GENOME STRUCTURE

LTR

prt-pol

LTR env
tas
orf-2

gag

FV Replication Cycle
rt

rt ? uncoat rt vDNA
CYTOPLASM

vCores vRNA rt

integ

NUCLEUS

ER budding

FV: Species Distribution

Species
Simian Bovine Feline Murine Otariidine Ovine Equine Human

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

SFV Prevalence in Primates Species

Prosimian Galago New World Primates Squirrel, Spider, Capuchin, Marmoset Old 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 Tropism

Exceptionally broad host range
Non-Primate Species
Chicken, Quail
Mouse Dog Cat

Cell Type

Tissue Origin

Fibroblast
Fibroblast Fibroblast Fibroblast

Embyro
Embryo, Tail Thymus Kidney

SFV Biology: Host Range and Cell Tropism

Primate Species
Monkey

Cell Type

Tissue Origin

Fibroblast Epithelial Macrophage Fibroblast Epithelial Lymphoid Macrophage Neural

Lung, Kidney Kidney Lung Lung Lung, Muscle T cells, B cells

Human

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 cells

Virus type dependent (Khan et al., submitted)

Prototype SFV-1 and SFV-2 > Naturally-occurring Isolates

Virus 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 Infection

Productive 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, Apoptosis Chronic 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 Primates

SFV 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 Animals

Immunocompetent 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 nonhuman primates.

SFV Experimental Infection in Animals

Transgenic 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 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 Pathogenesis
A 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 Pathogenesis
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, laboratoryadapted 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 probably due to saliva. No disease. SFV can infect humans due to accidental exposure (mostly due to bites; other?). No evidence of humanto-human transmission. No evidence of any virusassociated 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.