The U3 domains of the LTRs of foamy viruses contain cis-acting promoter elements (including the TATA box) which are recognized by cellular transcription factors. In addition, a second viral promoter (the internal promoter; IP) is located near the 3' end of the env gene (Fig. 1). Both promoters are dependent on the viral transactivator for full activity. Simian foamy viruses have U3 domains that are longer than those of all other retroviruses; thus, the potential is high for many cw-acting regulatory motifs. In the nuclei of infected cells, viral transcription initiates in the 5' LTR and in the IP, possibly in a temporally regulated manner. The IP appears to be a stronger promoter in infected cells (basal and trans-activated levels). Transcripts with the potential to code for the ORF region gene products originate predominantly from the IP. Subgenomic transcripts derived from either the 5' LTR or the IP are subject to complex splicing. All subgenomic viral transcripts which initiate in the 5' LTR have a short 5' leader (51 nucleotides) specified by the R region in the LTR. Both foamy virus promoters demonstrate very low basal levels of activity in transient expression assays, involving transfection of plasmids containing either the LTR or IP, into mammalian tissue culture cells. ORF 1 of SFV-1, SFV-3, SFVcpz and FeFV and bel-1 of HFV are transcriptional transactivator (tas) genes that act through cis-acting targets in the U3 domain of the respective LTR, or through sequences immediately 5' to the IP TATA box, to augment levels of viral transcripts. Mutational analysis of cloned viral genomes has demonstrated that the tas gene is required for viral replication. The target sequences for tas for each virus are upstream from the TATA box. SFV-1 Tas and HFV Bel-1 proteins interact directly with DNA target elements in each promoter. Foamy virus LTRs lack any significant homology with the LTRs of lentiviruses and other retroviruses; in addition, the tas genes are unrelated to the regulatory genes of other retroviruses. The Tas-responsive elements in the LTR and IP of each individual virus also show little overall homology other than a conserved TATA box. Thus, the mechanism of transactivation in the foamy virus system is fundamentally different from that for other viruses, and may be different for a given transactivator acting at the 5' LTR versus the IP. Functions for the potential genes encoded by the remaining ORFs (i.e. ORF 2; Bel-2,-3) are not yet known. Foamy viruses do not appear to contain a Rev/Rex axis as in the lentiviruses or oncoviruses. The additional ORFs are dispensable for replication in tissue culture cells; only the viral transactivator is required.

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