Clonality, latency and integration of HTLV-1 in vivo
© Bangham et al; licensee BioMed Central Ltd. 2013
Published: 19 September 2013
The HTLV-1 proviral load set point is the strongest correlate of the inflammatory and malignant diseases associated with HTLV-1. This set point appears to be determined by an equilibrium between virus-driven proliferation and CTL-mediated killing of HTLV-1-infected T cells. However, we do not know what determines the number, the abundance or the pathogenic potential of HTLV-1-infected T cell clones. In addition, the contribution of de novo infection to HTLV-1 persistence in the host remains uncertain.
We hypothesize that the genomic integration site (IS) of the HTLV-1 provirus determines the pattern and intensity of spontaneous proviral expression; the viral gene products in turn determine the rate of proliferation of the infected cells, and the rate of CTL-mediated killing. We aim to identify the factors that determine the integration site targeting, expression and abundance of the HTLV-1 provirus in natural infection.
Materials and methods
Each infected individual carries about 25,000 distinct clones of HTLV-1-infected T cells - between 100 and 1000 times more than previously believed.
HTLV-1 preferentially integrates into host DNA within 10 to 100 bases of binding sites for specific DNA-binding factors, notably P53 and STAT1. Spontaneous expression of HTLV-1 Tax is associated with antisense orientation of the provirus in the host gene and with specific transcription factor binding sites upstream or downstream of the provirus. Genomic hotspots of HTLV-1 integration are observed in cases of adult T-cell leukaemia/lymphoma (ATLL).
HTLV-1 preferentially survives in vivo when integrated in an acrocentric chromosome.
The results suggest that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection. These results open the way to tests of the molecular mechanisms of targeting, expression and clone proliferation in vivo.
This work was supported by the Wellcome Trust (UK) and Leukaemia and Lymphoma Research.
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