A defective human foamy provirus generated by pregenome splicing.

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.

Cell-Type-Specific Regulation of the Two Foamy Virus Promoters

“…Bet arises from a spliced message comprised of the first 88 amino acids of Tas and the entire bel2 ORF (35). Normally, the spliced bet message is derived from the IP (27), but at some frequency, LTR promoter transcripts are apparently spliced using the bet splice donor and acceptor sites, resulting in full-length SFVcpz(hu) genomes which can transcribe only bet and not tas (43). These defective genomes, termed SFVcpz(hu)⌬tas, have been suggested to play a role in mediating persistent infection in cells which normally undergo cytolytic infection (41).…”

“…Cells harboring SFVcpz(hu)⌬tas genomes produce large quantities of Bet upon infection with wild-type virus, providing an interesting link between Bet expression and the maintenance of persistent infection. It has been suggested that SFVcpz(hu)⌬tas acts as a defective interfering virus (22,41,43). The presence of large amounts of this form of FV in infected animals (9) and the accumulation of this viral form during experimental infection of rabbits (42) indicate that SFVcpz(hu)⌬tas may play an important role in FV persistence in vivo.…”

Development of Foamy Virus Vectors for Gene Therapy for Neurological Disorders and Other Diseases

“…Generated by the combination of the spliced mRNA of the Tas region and the Bel2 ORF (Linial, 2000), overexpression of Bet prevents the virus from infecting the host and inhibits viral integration at the initial stage of viral infection (Bock et al, 1998). A variant RNA can be generated by the LTR promoter, which has the ability to generate Bet protein fragments that, after reverse transcription, could induce the expression of a △Tas provirus (Saïb et al, 1993). Because of the deficiency of Tas in the provirus, △Tas plays a significant role in the preservation and latency of FVs, which clarifies that the LTR does not initiate the synthesis of viral protein, whereas the expression of Bet is induced by IP (Linial, 2000).…”

Persistent Infection with Primate Foamy Virus Type 1 Increases Human Immunodeficiency Virus Type 1 Cell Binding via a Bet-Independent Mechanism

“…Foamy viruses (FVs) are innocuous complex retroviruses that establish lifelong persistent infection in their hosts without inducing disease (13,15,17,19). Persistence of primate foamy virus type 1 (PFV-1), the prototype of FVs, is associated with accumulation of a defective homologous provirus, PFV⌬Tas, generated by alternative splicing of the wild-type genomic RNA, deleting a 301-bp intron in the viral transactivator tas gene (18,26,33), which negatively interferes with replication of its parental counterpart by production of the regulatory Bet protein (18,26,33). Interestingly, FV distribution among mammalian species mirrors that of lentiviruses (15,17), and although FVs display broad cell tropism, both infect T cells and macrophages (29).…”