title: CRISPR-mediated Activation of Latent HIV-1 Expression.
abstract: Complete eradication of HIV-1 infection is impeded by the existence of cells that harbor chromosomally integrated but transcriptionally inactive provirus. These cells can persist for years without producing viral progeny, rendering them refractory to immune surveillance and antiretroviral therapy and providing a permanent reservoir for the stochastic reactivation and reseeding of HIV-1. Strategies for purging this latent reservoir are thus needed to eradicate infection. Here, we show that engineered transcriptional activation systems based on CRISPR/Cas9 can be harnessed to activate viral gene expression in cell line models of HIV-1 latency. We further demonstrate that complementing Cas9 activators with latency-reversing compounds can enhance latent HIV-1 transcription and that epigenome modulation using CRISPR-based acetyltransferases can also promote viral gene activation. Collectively, these results demonstrate that CRISPR systems are potentially effective tools for inducing latent HIV-1 expression and that their use, in combination with antiretroviral therapy, could lead to improved therapies for HIV-1 infection.
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Prajit
authors.initials: P
authors.lastname: Limsirichai
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaj
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, California, USA.|Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA.|Department of Cell and Molecular Biology, University of California, Berkeley, Berkeley, California, USA.|Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
mesh_terms: D064113:CRISPR-Cas Systems; D002460:Cell Line; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics*; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D000072669:Gene Editing; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D010703:Phorbol Esters / Q000494:pharmacology; D011485:Protein Binding; D000094704:RNA, Guide, CRISPR-Cas Systems / Q000235:genetics; D015533:Transcriptional Activation; D014775:Virus Activation / Q000235:genetics*; D017735:Virus Latency
chemical_list: D056572:Histone Deacetylase Inhibitors; D010703:Phorbol Esters; D000094704:RNA, Guide, CRISPR-Cas Systems; C070999:prostratin