The impact of HTLV-1 expression on the 3D structure and expression of host chromatin.

A typical HTLV-1-infected individual carries >10⁴ different HTLV-1-infected T cell clones, each with a single-copy provirus integrated in a unique genomic site. We previously showed that the HTLV-1 provirus causes aberrant transcription in the flanking host genome and, by binding the chromatin architectural protein CTCF, forms abnormal chromatin loops with the host genome. However, it remained unknown whether these effects were exerted simply by the presence of the provirus or were induced by its transcription. To answer this question, we sorted HTLV-1-infected T-cell clones into cells positive or negative for proviral plus-strand expression, and then quantified host and provirus transcription using RNA-seq, and chromatin looping using quantitative chromosome conformation capture (q4C), in each cell population. We found that proviral plus-strand transcription induces aberrant transcription and splicing in the flanking genome but suppresses aberrant chromatin loop formation with the nearby host chromatin. Reducing provirus-induced host transcription with an inhibitor of transcriptional elongation allows recovery of chromatin loops in the plus-strand-expressing population. We conclude that aberrant host transcription induced by proviral expression causes temporary, reversible disruption of chromatin looping in the vicinity of the provirus. Author summary: The human T cell leukemia virus HTLV-1 causes an aggressive leukemia or lymphoma in ~5% of people infected with the virus, and a further 1–4% develop a chronic inflammatory disease that leads to progressive paralysis of the legs. HTLV-1 is a retrovirus, like HIV, and these viruses insert themselves–as a 'provirus'—into the DNA of the T lymphocytes that they infect: this is largely why the viruses are very difficult to eradicate. The provirus remains dormant for most of the time, but it can be reactivated when the T cell meets a change in temperature or pH, or a number of other conditions. We recently discovered that HTLV-1, when it is integrated into the host DNA, changes the 3D structure of the genome in the infected cell, and interferes with the normal function of the host genes that lie near HTLV-1 in the genome. What we have now found is that the change in the 3D structure of the genome is caused simply by the presence of the provirus, but that when the provirus is reactivated the 3D structural changes are temporarily removed, and nearby host genes can be abnormally activated by the provirus. [ABSTRACT FROM AUTHOR]