Symmetrical recognition of cellular DNA target sequences during retroviral integration

Abstract

I ntegration of the retrovirus DNA genome into host chromosomes is essential for viral replication. After virus infection of the cell, synthesis of viral cDNA occurs by reverse transcription of the viral RNA genome. Integration of the viral DNA genome into cellular DNA is catalyzed by the viral integrase (IN) encapsulated within the infecting virus particle. Viral DNA integration has different consequences for the host. Integration of HIV type 1 (HIV-1) results in virus spread giving rise to the pathology of HIV-1/AIDS that can be suppressed by combinational drug therapies. In animal model systems, the integrated provirus of murine leukemia virus (MLV) and avian sarcoma-leukemia virus (ASLV) DNA either is transcribed to produce virus particles or is silenced by host cellular mechanisms, or, on rare occasions, may modify cellular protooncogenes that can result in different forms of cancers. In this issue of PNAS, Holman and Coffin (1) studied DNA sequences at the sites of integration of HIV-1, MLV, and ASLV viral genomes within the human genome. The evaluation of this collection of nucleotide sequences was made possible by coupling the known human genome sequence with the recent cloning and sequencing of several thousand viral DNA integration sites resulting from infection of human cells by these three retroviruses (2-5). Analysis showed significant base preferences at and near integration sites. Integration of the retrovirus DNA genome by IN occurs in the context of viral nucleoprotein complexes termed preintegration complexes (PICs) (6). Do PICs of HIV-1, MLV, and ASLV select distinct chromosomal regions in the human genome (2-5) for integration of their viral genomes? All of the chromosomes represented nearly equal targets for viral DNA integration with all three viruses. HIV-1 PIC favored integrating its viral genome inside genes (2-4). MLV preferred integrating into or near …