期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：44
页码：18786-18791
DOI：10.1073/pnas.0905859106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Integration of HIV-1 linear DNA into the host chromatin is an essential step in the viral life cycle. However, the majority of reverse-transcribed, nuclear-imported viral genomes remain episomal, either as linear or circular DNA. To date, these nonintegrated viral genomes are largely considered "dead-end products" of reverse transcription. Indeed, limited gene expression from nonintegrated HIV-1 has been reported, although the mechanism that renders nonintegrating HIV-1 genomes incapable of supporting efficient viral replication has not been fully elucidated. Here, we demonstrate that nonintegrating HIV-1 and HIV-1-based vector genomes are organized into chromatin structures and enriched with histone modifications typical of transcriptionally silenced chromatin. Gene expression and replication of nonintegrating HIV-1 was notably increased in vitro upon exposure to histone deacetylase inhibitors (HDACi) in the form of various short-chain fatty acids (SCFAs) known to be endogenously produced by normal microbial-gut flora. Furthermore, we demonstrated genetic and functional crosstalk between episomal and integrated vector/viral genomes, resulting in recombination between integrated and nonintegrated HIV-1, as well as mobilization of episomal vector genomes by productive viral particles encoded by integrated viral genomes. Finally, we propose a mechanism describing the role of episomal HIV-1 forms in the viral life cycle in a SCFA-rich gut environment.
