Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection

Kantor, Boris; Ma, Hong; Webster‐Cyriaque, Jennifer; Monahan, Paul E.; Kafri, Tal

doi:10.1073/pnas.0905859106

Cited by 85 publications

(118 citation statements)

References 39 publications

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“…Intriguingly, it has been reported that similar numbers of integrated and unintegrated HIV-1 templates transcribe RNA (23). It is generally observed that uDNA gene expression is higher in nonproliferating cells than in proliferating cells, perhaps owing to a lack of dilution of uDNA templates and their RNA and protein products (17,(24)(25)(26)(27). The virion-associated Vpr protein transactivates uDNA, enhancing expression of early viral proteins in infected activated CD4 ϩ T cells (28,29).…”

mentioning

confidence: 99%

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

Trinité

Ohlson

Voznesensky

et al. 2013

J Virol

116

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cells. We found that infection of cytokine-treated resting CD4؉ T cells in the presence of raltegravir or with integrase active-site mutant HIV-1 yielded de novo virus production following subsequent T cell activation. Infection with integration-competent HIV-1 naturally generated a population of cells generating virus from unintegrated DNA. Latent infection persisted for several weeks and could be activated to virus production by a combination of a histone deacetylase inhibitor and a protein kinase C activator or by T cell activation. HIV-1 Vpr was essential for unintegrated HIV-1 gene expression and de novo virus production in this system. Bypassing integration by this mechanism may allow the preservation of genetic information that otherwise would be lost.

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mentioning

confidence: 99%

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

Trinité

Ohlson

Voznesensky

et al. 2013

J Virol

116

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“…Differences in transcription between integrated and unintegrated HIV-1 may be due to the fact that unintegrated HIV-1 cDNA is organized into chromatin structures, with histone modifications typical of silenced chromatin (23). Additionally, the low levels of Rev synthesized prior to integration may also limit the translation of unspliced viral RNA transcripts and ultimate expression of late gene products (58).…”

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confidence: 99%

Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef

Sloan

Kuhl

Donahue

et al. 2011

J Virol

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“…That DNA episomes of viral origin (Levrero et al, 2009;You 2010;Nevels et al, 2011) or otherwise can become ''chromatinized'' and thus acquire nucleosome-like properties soon upon entry into the nucleus is well established. Whether this assembly of protein-DNA complexes promotes or represses gene expression through chromatin opening or compaction, respectively, is contingent upon a plethora of variables that are likely to include the nuclear domain localization of the episomes and their cis-and trans-acting elements, as well as the physiological statuses of the host cells (Bishop et al, 2006;Riu et al, 2007;Kantor et al, 2009;Ross et al, 2009;Ross et al, 2011). Ultimately, these tilt the balance between conducive versus repressive high-order epigenetic mechanisms such as those involving histone post-translational modifications of which acetylation, methylation, and ubiquitination are but a few examples (Cedar and Bergman, 2009;Bannister and Kouzarides, 2011).…”

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confidence: 99%

Histone Deacetylase Inhibition Activates Transgene Expression from Integration-Defective Lentiviral Vectors in Dividing and Non-Dividing Cells

2013

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Integration-defective lentiviral vectors (IDLVs) are being increasingly deployed in both basic and preclinical gene transfer settings. Often, however, the IDLV transgene expression profile is muted when compared to that of their integration-proficient counterparts. We hypothesized that the episomal nature of IDLVs turns them into preferential targets for epigenetic silencing involving chromatin-remodeling histone deacetylation. Therefore, vectors carrying an array of cis-acting elements and transcriptional unit components were assembled with the aid of packaging constructs encoding either the wild-type or the class I mutant D116N integrase moieties. The transduction levels and transgene-product yields provided by each vector class were assessed in the presence and absence of the histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A. To investigate the role of the target cell replication status, we performed experiments in growth-arrested human mesenchymal stem cells and in post-mitotic syncytial myotubes. We found that IDLVs are acutely affected by HDACs regardless of their genetic makeup or target cell replication rate. Interestingly, the magnitude of IDLV transgene expression rescue due to HDAC inhibition varied in a vector backbone-and cell type-dependent manner. Finally, investigation of histone modifications by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) revealed a paucity of euchromatin marks distributed along IDLV genomes when compared to those measured on isogenic integration-competent vector templates. These findings support the view that IDLVs constitute preferential targets for epigenetic silencing involving histone deacetylation, which contributes to dampening their full transcriptional potential. Our data provide leads on how to most optimally titrate and deploy these promising episomal gene delivery vehicles.

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Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection

Cited by 85 publications

References 39 publications

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef

Histone Deacetylase Inhibition Activates Transgene Expression from Integration-Defective Lentiviral Vectors in Dividing and Non-Dividing Cells

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