Spatial and Genomic Correlates of HIV-1 Integration Site Targeting

• Main Authors: Bedwell, G.J (Author), Engelman, A.N (Author), Singh, P.K (Author)
• Format: Article
• Language: English
• Published: MDPI 2022
• Subjects: acquired immune deficiency syndrome; Article; binding kinetics; capsid protein; CD4+ T lymphocyte; chemokine receptor CCR5; chromatin; chromatin immunoprecipitation; chromosome 20; cleavage and polyadenylation specificity factor; CPSF6; equine infectious anemia; gene expression; genetic marker; genetic transcription; genomic DNA; HIV/AIDS; host factor; Human immunodeficiency virus 1; Human immunodeficiency virus infection; immunoprecipitation; integrase; intron; Lamina-associated domains; LEDGF/p75; lens epithelium derived growth factor; molecular dynamics; nuclear speckle; Nuclear speckles; retroposon; Retroviral integration; RNA polymerase II; Speckle-associated domains; transcription factor; virus capsid; virus DNA
• Online Access: View Fulltext in Publisher

 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-asso-ciated 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 target-ing. 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 inte-gration. 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 contribu-tions of capsid and integrase interactions with respective CPSF6 and LEDGF/p75 host factors in these HIV-1 integration targeting preferences. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.