Foamy virus biology and its application for vector development

Abstract

Spuma- or foamy viruses (FV), endemic in most non-human primates, cats, cattle and horses, comprise a special type of retrovirus that has developed a replication strategy combining features of both retroviruses and hepadnaviruses. Unique features of FVs include an apparent apathogenicity in natural hosts as well as zoonotically infected humans, a reverse transcription of the packaged viral RNA genome late during viral replication resulting in an infectious DNA genome in released FV particles and a special particle release strategy depending capsid and glycoprotein coexpression and specific interaction between both components. In addition, particular features with respect to the integration profile into the host genomic DNA discriminate FV from orthoretroviruses. It appears that some inherent properties of FV vectors set them favorably apart from orthoretroviral vectors and ask for additional basic research on the viruses as well as on the application in Gene Therapy. This review will summarize the current knowledge of FV biology and the development as a gene transfer system.

Keywords: Fanconi Anemia; Foamyviruses; LAD; retroviral vectors.

Figure 1

Schematic overview of the spuma- or foamy viruses (FV) replication cycle. Electron micrographs (courtesy of H. Zentgraf and J. Krijnse-Locker, Heidelberg) of different steps of FV particle morphogenesis are shown in the upper panel.

Figure 2

Spuma- or foamy viruses (FV) RNA and DNA genomic organization. Schematic outline of the FV proviral genome (top) and the genomic (middle) and subgenomic transcripts generated by cellular RNA polymerase from long terminal repeat (LTR) and internal promoter (IP). c: cap structure; An: poly-alanine; CAS: cis-acting sequence; PPT: poly purine tract: U3: LTR unique 3′ region; R: LTR repeat region; U5: LTR unique 5′ region; PR: protease domain; RT/RH: reverse transcriptase-RNAse H domain; IN: integrase domain; LP: leader peptide domain; SU: surface domain; TM: transmembrane domain.

Figure 3

The spuma- or foamy viruses (FV) structural gene products. Schematic of domain organization of Prototype FV (PFV) Gag (A), PFV Pol (B), and PFV Env (C). (D) Proposed membrane topology and oligomeric organization of PFV Env. (E) Schematic outline of a PFV particle. CC: coiled-coil motif; L: PSAP late-assembly (L)-domain motif; A: YXXLGL assembly domain motif; GR: glycine-arginine rich box; PR: protease domain; RT: reverse transcriptase domain; RH: RNAse H domain; IN: integrase domain; h: hydrophobic domain of the leader peptide (LP); FP: fusion peptide of the transmembrane subunit (TM); MSD: membrane-spanning domain of the TM subunit; N: N-terminus; C: C-terminus.

Figure 4

Third generation Prototype FV (PFV) vector system. Schematic outline of the third generation (A) transfer vector PV and (B) packaging expression vectors for codon-optimized (co) Gag (PG), coPol (PP), and coEnv (PE). CMV: cytomegalovirus immediate early promoter; R: LTR repeat region; U5: LTR unique 5′ region; ΔU3: enhancer-promoter deleted LTR unique 3′ region; Prom: internal heterologous promoter; CAS: cis-acting sequence; SD: splice donor; SA: splice acceptor.