Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection.
The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T c...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1003271 |
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| author | Anat Melamed Daniel J Laydon Nicolas A Gillet Yuetsu Tanaka Graham P Taylor Charles R M Bangham |
| author_facet | Anat Melamed Daniel J Laydon Nicolas A Gillet Yuetsu Tanaka Graham P Taylor Charles R M Bangham |
| author_sort | Anat Melamed |
| collection | DOAJ |
| description | The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection. |
| format | Article |
| id | doaj-art-b42442e82b3b48c5a42e16c37962c0a0 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2013-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-b42442e82b3b48c5a42e16c37962c0a02025-08-20T02:34:16ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-03-0193e100327110.1371/journal.ppat.1003271Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection.Anat MelamedDaniel J LaydonNicolas A GilletYuetsu TanakaGraham P TaylorCharles R M BanghamThe regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection.https://doi.org/10.1371/journal.ppat.1003271 |
| spellingShingle | Anat Melamed Daniel J Laydon Nicolas A Gillet Yuetsu Tanaka Graham P Taylor Charles R M Bangham Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. PLoS Pathogens |
| title | Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. |
| title_full | Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. |
| title_fullStr | Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. |
| title_full_unstemmed | Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. |
| title_short | Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. |
| title_sort | genome wide determinants of proviral targeting clonal abundance and expression in natural htlv 1 infection |
| url | https://doi.org/10.1371/journal.ppat.1003271 |
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