Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection.
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.
Gene Therapy Center, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
Boris
B
Kantor
Hong
H
Ma
Jennifer
J
Webster-Cyriaque
Paul E
PE
Monahan
Tal
T
Kafri
D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005232:Fatty Acids, Volatile / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D020868:Gene Silencing / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics; D016679:Genome, Viral / Q000187:drug effects / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000821:virology*; D019427:HIV Integrase / Q000172:deficiency / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D009000:Monocytes / Q000166:cytology; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016662:Virus Integration / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D002843:Chromatin; D005232:Fatty Acids, Volatile; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D019427:HIV Integrase; D006655:Histone Deacetylases