# Presentation: 090877

## 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***

***env***

***tas***

**orf-2**

**LTR**

***   ******gag***

**      ****SFV GENOME STRUCTURE**

## FV Replication Cycle

- <date/time>

**FV Replication Cycle**

**rt**

**          ****ER**
**     ****budding**

**CYTOPLASM**

**NUCLEUS**

**rt**

**rt**

**rt**

**integ**

**uncoat**

**vDNA**

**vRNA**

**vCores**

**?**

**?**

## FV: Species Distribution

**Species      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 virus**
**Ovine                Sheep foamy virus**
**Equine              Horse foamy virus (EFV)**
**Human             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             Cell Type            Tissue Origin**
**Species**
**Chicken, Quail****                 Fibroblast               Embyro**
**Mouse    ****                           Fibroblast               Embryo, Tail**
**Dog  ****                                 Fibroblast              Thymus**
**Cat    ****                                Fibroblast              Kidney **

## SFV Biology: Host Range and Cell Tropism

**Primate                 Cell Type         Tissue Origin**
**Species**
**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 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 non-human 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, 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  **
**         ****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.**