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A defective human foamy provirus generated by pregenome splicing
1CNRS UPR 43, Rétrovirus et rétrotransposons des vertébrés, Centre Hayem, Hôpital St Louis, Paris, France.
Abstract:
Foamy viruses are a group of retroviruses of complex structure which were thought to be non-pathogenic. The recent demonstration of neurological diseases in mice transgenic for human foamy virus (HFV) and the high prevalence of HFV sequences in Graves' disease question this idea. By PCR, we have detected HFV sequences with a non-random deletion in the bel1 transactivator gene in other autoimmune conditions. Sequence analysis revealed that this deleted area corresponds to the excision of a known intron in bet, one of HFV's regulatory genes. The same phenomenon was observed in both acute and chronic infections, in vitro or in vivo, although the deleted forms were distinctly more abundant in chronic states. The viral DNA containing the bel1 deletion is apparently part of an otherwise complete genome, strongly suggesting that this provirus derives from the reverse transcription of a spliced pregenomic RNA. Bel1-spliced provirus was shown to be defective when transfected into permissive cells. However, co-expression with the Bel1 transactivator led to functional trans-complementation and formation of viral particles. Splicing of the genome may be an important factor in HFV biology: genomes with the deletion may either interfere with wild-type virus expression or alter host cell functions through background expression of viral regulatory proteins.
Insights
Human foamy virus (HFV) may be pathogenic, contrary to prior beliefs. Researchers found spliced HFV genomes with a bel1 deletion in autoimmune diseases, suggesting a role in disease pathogenesis.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Foamy viruses, including human foamy virus (HFV), were historically considered non-pathogenic.
- Recent findings suggest HFV may be linked to neurological diseases and autoimmune conditions like Graves' disease.
Purpose of the Study:
- To investigate the presence and significance of HFV sequences in autoimmune conditions.
- To explore the molecular mechanisms behind potential HFV-induced pathogenicity.
Main Methods:
- Polymerase Chain Reaction (PCR) to detect HFV sequences.
- Sequence analysis to identify genetic deletions and characterize viral RNA.
- Transfection assays to assess viral infectivity and complementation.
Main Results:
- HFV sequences with a specific deletion in the bel1 transactivator gene were detected in various autoimmune conditions.
- This deletion corresponds to the excision of an intron in the HFV bet gene, observed in both acute and chronic infections, and more abundant in chronic states.
- The bel1-deleted provirus originates from spliced RNA and is replication-defective but can be functionally complemented by the Bel1 transactivator.
Conclusions:
- Splicing of the HFV genome, leading to bel1 deletion, is a significant biological event.
- This spliced form may interfere with wild-type HFV replication or alter host cell functions, contributing to disease.
- HFV's pathogenic potential warrants further investigation, particularly in the context of autoimmune diseases.