Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection

PLoS Pathogens

Charles C Berry¹  Sridhar Hannenhalli²  Jeremy Leipzig³  Heather Marshall³  Angela Ciuffi³  Masahiro Yamashita⁴  Michael Emerman⁴  Joseph R Ecker⁵  Paul Shinn⁵  Mary K Lewinski⁶  Frederic D Bushman⁶  Gregory Crawford⁷  Francis Collins⁷ 

[1] Department of Family/Preventive Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America;Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America;Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America;Divisions of Human Biology and Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Genomic Analysis Laboratory, The Salk Institute, La Jolla, California, United States of America;Infectious Disease Laboratory, The Salk Institute, La Jolla, California, United States of America;National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: HIV;    DNA methylation;    DNA transcription;    Deoxyribonucleases;    DNA sequence analysis;    DNA-binding proteins;    Human genomics;    Retroviruses;   

DOI  :  10.1371/journal.ppat.0020060

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV) integrates preferentially within active transcription units, whereas murine leukemia virus (MLV) integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN) coding region into HIV (to make HIVmIN) caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN) further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag) displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I–hypersensitive sites (i.e., +/− 1 kb), and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins.

【 授权许可】

CC BY