Spatially clustered loci with multiple enhancers are frequent targets of HIV-1 integration

Abstract

HIV-1 recurrently targets active genes and integrates in the proximity of the nuclear pore compartment in CD4 + T cells. However, the genomic features of these genes and the relevance of their transcriptional activity for HIV-1 integration have so far remained unclear. Here we show that recurrently targeted genes are proximal to super-enhancer genomic elements and that they cluster in specific spatial compartments of the T cell nucleus. We further show that these gene clusters acquire their location during the activation of T cells. The clustering of these genes along with their transcriptional activity are the major determinants of HIV-1 integration in T cells. Our results provide evidence of the relevance of the spatial compartmentalization of the genome for HIV-1 integration, thus further strengthening the role of nuclear architecture in viral infection.

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

“…However, given the limited number of genes in each of the subgroups of Group 6, we treated them as a single group to increase statistical power. Remarkably, the large number of proviruses detected in Groups 4-6 (Intragenic) compared to Groups 1-3 (Intergenic) is consistent with previous studies examining integration sites ex vivo and in patient samples, highlighting HIV integrations in intronic regions of highly transcribed genes (Schroder et al 2002;Ikeda et al 2007;Maldarelli et al 2014;Lucic et al 2019).…”

“…HIV displays specific preference to integrate into genes proximal to high density of enhancers (Lucic et al 2019), which can potentially regulate proviral transcription. Enhancers are short DNA sequences that act as transcription factor binding hubs controlling key transcriptional programs by finetuning target gene promoter activity across vast linear distances (Whyte et al 2013;Kim and Shiekhattar 2015;Li et al 2016).…”

“…3B), thus proposing that intragenically positioned proviruses may benefit from both its positions nearby to regulatory elements such as gene promoters and SE. Together, the preference for HIV to integrate into genes proximal to SE (Lucic et al 2019) may have the dual benefit of increasing proviral transcriptional levels.…”

“…Over the past two decades, great efforts have been made for elucidating how HIV integrates into the human genome and how HIV proviral transcription normally operates (Ott et al 2011;Mbonye and Karn 2014;Hughes and Coffin 2016;Mbonye and Karn 2017;Michieletto et al 2019;Morton et al 2019). Interestingly, in CD4 + T cells of patient samples and in ex vivo studies, HIV preferentially integrates into chromatin-accessible sites located near the nuclear pore and within or near transcriptionally active regions (Schroder et al 2002;Cohn et al 2015;Marini et al 2015;Lucic et al 2019). However, integrated proviruses are detected on every human chromosome, in various chromatin landscapes (euchromatic and heterochromatic), and at different locations (intergenic or intragenic) and orientations (sense, divergent or convergent) respective to human genes and regulatory elements.…”

Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter

“…We hypothesized that a shift in loop formation towards URE and AsPr instead of PrPr might account for the shift from sense towards antisense transcription in T-cell progenitors (Fig.1e-f). To test this idea, we examined chromosomal conformation capture sequencing (Hi-C) data from early T-lymphoid (Jurkat) 19 and myeloid (HL-60) 20 with an URE-PrPr interaction (Fig.4a). We therefore performed in-depth analyses of interacting PU.1 chromosomal structures in both cell lines using chromosomal conformation capture assays (3C) (Fig.4b).…”