Abstract
Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome. However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. Once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle.
Highlights
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Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome[1,2,3,4]
We show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore
Summary
Was a marked reduction in HIV-1 integration (Fig. 2k), and the majority of the signals labelled unintegrated viral DNA16: 72% and 77% of the FISH signals were in zones 2 and 3 for the LEDGF/p75 and Nup[153] knockdowns, respectively (Fig. 2l). To understand the chromatin features of RIGs, we compared the available data from chromatin immunoprecipitation sequencing (ChIP-seq) obtained in CD41 T cells for RIGs22, cold genes (defined as transcriptionally inactive genes never targeted by HIV-1; F.M. and A.R., unpublished observations) and a list of genes corresponding to the 1,000 most expressed (active) and 1,000 least expressed (silent) genes from the GNF SymAtlas[13]. Markers of facultative (H3K9me2) and constitutive (H3K9me[3] and H3K27me3) chromatin were found enriched both on cold genes (where HIV-1 never integrates) and on silent genes, but not on RIGs (Extended Data Fig. 5). Active genes and RIGs had a superimposable distribution of H3K4me[2], which is enriched at the lamin-associated domain (LAD) borders[5] (Fig. 3f).
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