A defective human foamy provirus generated by pregenome splicing.

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.