Key result
The first 151 nucleotides of the human foamy virus LTR R region are critical for Gag and Pol protein expression, acting post-transcriptionally in the nucleus to enhance cytoplasmic mRNA utilization.
The HFV R region is critical for Gag and Pol protein expression by acting in the nucleus to modify the cytoplasmic fate of target mRNA, suggesting a common posttranscriptional activation mechanism among distinct retrovirus families.
Extends retroviral mRNA regulation insights; hypothesis-generating for shared mechanisms across families and requires human-cell validation before any translational consideration.
It has been suggested that sequences located within the 5' noncoding region of human foamy virus (HFV) are critical for expression of the viral Gag and Pol structural proteins. Here, we identify a discrete approximately 151-nucleotide sequence, located within the R region of the HFV long terminal repeat, that activates HFV Gag and Pol expression when present in the 5' noncoding region but that is inactive when inverted or when placed in the 3' noncoding region. Sequences that are critical for the expression of both Gag and Pol include not only the 5' splice site positioned at +51 in the R region, which is used to generate the spliced pol mRNA, but also intronic R sequences located well 3' to this splice site. Analysis of total cellular gag and pol mRNA expression demonstrates that deletion of the R region has little effect on gag mRNA levels but that R deletions that would be predicted to leave the pol 5' splice site intact nevertheless inhibit the production of the spliced pol mRNA. Gag expression can be largely rescued by the introduction of an intron into the 5' noncoding sequence in place of the R region but not by an intron or any one of several distinct retroviral nuclear RNA export sequences inserted into the mRNA 3' noncoding sequence. Neither the R element nor the introduced 5' intron markedly affects the cytoplasmic level of HFV gag mRNA. The poor translational utilization of these cytoplasmic mRNAs when the R region is not present in cis also extended to a cat indicator gene linked to an internal ribosome entry site introduced into the 3' noncoding region. Together these data imply that the HFV R region acts in the nucleus to modify the cytoplasmic fate of target HFV mRNA. The close similarity between the role of the HFV R region revealed in this study and previous data (M. Butsch, S. Hull, Y. Wang, T. M. Roberts, and K. Boris-Lawrie, J. Virol. 73:4847--4855, 1999) demonstrating a critical role for the R region in activating gene expression in the unrelated retrovirus spleen necrosis virus suggests that several distinct retrovirus families may utilize a common yet novel mechanism for the posttranscriptional activation of viral structural protein expression.
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Russell et al. (2001) studied Human Foamy Virus (HFV) gene expression. HFV LTR R region sequences vs. Plasmids lacking the R region or with inverted/repositioned R regions was evaluated on Gag and Pol protein expression and mRNA levels. The first 151 nucleotides of the human foamy virus LTR R region are critical for Gag and Pol protein expression, acting post-transcriptionally in the nucleus to enhance cytoplasmic mRNA utilization.
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