This is consistent with previous data regarding the yeast protein CUS2, which is structurally similar to human Tat-SF1. Both proteins contain two RRMs in their N-terminus, but Tat-SF1 has a large acidic C-terminus that is absent in CUS2. The first RRMs of these proteins are 37% identical and 59% similar. The second RRMs are 30% identical and 56% similar. CUS2 associates with U2 snRNA in splicing extracts and co-immunoprecipitates PRP11, which is a subunit of SF3a. When anti-Tat-SF1 antibodies were used for immunoprecipitation, the human homologue of PRP11, SF3a66,GSI-IX was also immunoprecipitated. An effect of Tat-SF1 depletion on HIV-1 RNA ratios is also consistent with recent unpublished data from our laboratory that demonstrate that Tat-SF1 depletion changes the relative levels many alternatively spliced transcripts in human cells without affecting the total amount of these transcripts. An effect on splicing could be direct, as proposed for CUS2. Thus, Tat-SF1 could help in the folding and activity of splicing factors such as U2 snRNAs, but it could also rework the folding of the HIV transcripts leading to efficient splicing. Tat-SF1 may also have an indirect effect on HIV-1 pre-mRNA splicing by regulating the processing of transcripts encoding other HIV dependency factors. In fact, we analyzed the HDFs published by the Brass et al. and Konig et al. screens and found approximately 2-fold enrichment over chance alone in genes that also had evidence of Tat-SF1-regulated alternative splicing. Tat-SF1 could also be involved in virion packaging. The decrease in infectivity in Tat-SF1 depleted cells could be explained if Tat-SF1 was a chaperone protein, helping fold the viral pre-mRNA genome into productive virions. Such a role in viral RNA packaging would be consistent with Tat-SF1’s role in influenza virus replication. Tat-SF1 was identified as a stimulatory host factor,Adriamycin possibly aiding in the formation of RNA-nucleoprotein complexes by acting as a molecular chaperone. It remains to be seen whether Tat-SF1 binds HIV-1 pre-mRNA and helps package viral genomes into virions. An increase in the unspliced RNA upon Tat-SF1 knockdown could also be explained by Tat-SF1 having a role in RNA export from the nucleus, although this has not yet been tested.