Abstract
HIV-1 integrase and capsid proteins interact with host proteins to direct preintegration complexes to active transcription units within gene-dense regions of chromosomes for viral DNA integration. Analyses of spatially-derived genomic DNA coordinates, such as nuclear speckle-associated domains, lamina-associated domains, super enhancers, and Spatial Position Inference of the Nuclear (SPIN) genome states, have further informed the mechanisms of HIV-1 integration targeting. Critically, however, these different types of genomic coordinates have not been systematically analyzed to synthesize a concise description of the regions of chromatin that HIV-1 prefers for integration. To address this informational gap, we have extensively correlated genomic DNA coordinates of HIV-1 integration targeting preferences. We demonstrate that nuclear speckle-associated and speckle-proximal chromatin are highly predictive markers of integration and that these regions account for known HIV biases for gene-dense regions, highly transcribed genes, as well as the mid-regions of gene bodies. In contrast to a prior report that intronless genes were poorly targeted for integration, we find that intronless genes in proximity to nuclear speckles are more highly targeted than are spatially-matched intron-containing genes. Our results additionally highlight the contributions of capsid and integrase interactions with respective CPSF6 and LEDGF/p75 host factors in these HIV-1 integration targeting preferences.
Highlights
Retroviral preintegration complexes (PICs) display variable preferences for genomic features associated with active versus repressive regions of chromatin during integration
To address the potential roles of integration targeting cofactors lens epithelium-derived growth factor (LEDGF)/p75 and cleavage and polyadenylation specificity factor 6 (CPSF6) in the resulting phenotypes, we analyzed integration site datasets derived from factor-depleted cells or from cells infected with capsid protein (CA) mutant viruses that are defective for CPSF6 binding [6,15]
While not targets of clinical infection, HEK293T and Jurkat T cells were chosen due to accessibility of complementary datasets derived from LEDGF/p75- and CPSF6-depleted cells, or from cells infected with CA mutant viruses that are defective for CPSF6 binding [6,13,15]
Summary
Retroviral preintegration complexes (PICs) display variable preferences for genomic features associated with active versus repressive regions of chromatin during integration (for recent reviews, see [1,2]). HIV-1 integration disfavors gene-sparse heterochromatic regions such as centromeric alphoid repeats [8] and lamina-associated domains (LADs) [9,10], as well as regions proximal to repressive epigenetic marks such as H3K9me2/3 and H3K27me3 [4,5,6]. Integration targeting preferences have been linked to speckle-associated domains (SPADs) [14,15] and Speckle and Interior Active 1 SPIN states [13] that typically localize distal from the nuclear envelope [11,12]. Chromatin regions associated with peripheral nuclear markers, such as LADs [9,10] and Near Lamina 1-2 and Lamina SPIN states [13], are strongly disfavored for HIV-1 integration
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