Genome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection

PLoS Pathogens

Charles R. M. Bangham¹  Nicolas A. Gillet²  Anat Melamed²  Daniel J. Laydon²  Graham P. Taylor³  Yuetsu Tanaka⁴ 

[1] Department of Genitourinary Medicine and Communicable Diseases, Wright-Fleming Institute, Imperial College London, London, United Kingdom;Department of Immunology, Wright-Fleming Institute, Imperial College London, London, United Kingdom;Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan;Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), Liège, Belgium

关键词: Cloning;    HTLV-1;    DNA transcription;    T cells;    DNA methylation;    Transcription factors;    Human genomics;    Genomic libraries;   

DOI  :  10.1371/journal.ppat.1003271

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY