Histone deacetylase inhibitors induce complex host responses that contribute to differential potencies of these compounds in HIV reactivation

Beliakova-Bethell, Nadejda; Mukim, Amey; White, Cory H.; Deshmukh, Savitha; Abewe, Hosiana; Richman, Douglas D.; Spina, Celsa A.

doi:10.1074/jbc.ra118.005185

Cited by 23 publications

(46 citation statements)

References 56 publications

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“…Among the remaining seven LRAs, three remarkedly modulated the most genes: romidepsin (5798 genes, 33.7% of all expressed genes in the samples), followed by AZD5582 (4512, 30.0%) and SAHA, (3218, 19.0%) also in the Beliakova-Bethell et al [ 42 ] study samples. All three were associated with the differential expression of more than 10% of all expressed genes in the sample, whereas all others LRAs modulated much less genes (disulfiram: 473, 2.8%; ingenol B: 443, 3.0%; Il-7: 199, 1.2% and bryostatin: 20, 0.2%; results summarized in Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Following duplicates removal, abstracts were screened, producing a shortlist of ten studies for further review to check if they met the inclusion criteria mentioned previously. From those, six were reanalyzed, being five studies with published reports [ 40 , 41 , 42 , 43 , 44 ]. We could not ascertain if the remaining project, submitted publicly by the contributor Vallejo-Gracia on April 2019, which was retrieved from the search through GEO database has already been published.…”

Section: Resultsmentioning

confidence: 99%

“…The third study, from Beliakova-Bethell et al (GSE114883) [ 42 ] used samples of primary CD4+ T cells from HIV-1-negative blood donors which were then infected through a laboratory bystander infection model [ 49 ]. This study included 12 samples from four donors, being four controls and eight LRA-treated (one control sample per donor—treated with DMSO only and two treated samples per donor—with SAHA or romidepsin).…”

Section: Resultsmentioning

confidence: 99%

“…Beliakova-Bethell et al [ 42 ] stimulated CD4+ T cells with SAHA or romidepsin and compared the modulated genes by these two agents with the HIV-1 Human Protein Interaction Database and obtained a match of 64 genes overall (up- and down-regulated by both SAHA and romidepsin and up- and down-regulated by either of them alone). The genes CDK2 , HSPA2, TNF and RCOR2 were up-regulated and the genes IL16, ITK, MX2, NCOA2 and PIK3CG were down-regulated by both romidepsin and SAHA and were present in our intersection list.…”

Section: Discussionmentioning

confidence: 99%

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Reanalysis of Gene Expression Profiles of CD4+ T Cells Treated with HIV-1 Latency Reversal Agents

2020

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The human immunodeficiency virus (HIV-1) causes a progressive depletion of CD4+ T cells, hampering immune function. Current experimental strategies to fight the virus focus on the reactivation of latent HIV-1 in the viral reservoir to make the virus detectable by the immune system, by searching for latency reversal agents (LRAs). We hypothesize that if common molecular pathways elicited by the presence of LRAs are known, perhaps new, more efficient, “shock-and-kill” strategies can be found. Thus, the objective of the present study is to re-evaluate RNA-Seq assays to find differentially expressed genes (DEGs) during latency reversal via transcriptome analysis. We selected six studies (45 samples altogether: 16 negative controls and 29 LRA-treated CD4+ T cells) and 11 LRA strategies through a systematic search in Gene Expression Omnibus (GEO) and PubMed databases. The raw reads were trimmed, counted, and normalized. Next, we detected consistent DEGs in these independent experiments. AZD5582, romidepsin, and suberanilohydroxamic acid (SAHA) were the LRAs that modulated most genes. We detected 948 DEGs shared by those three LRAs. Gene ontology analysis and cross-referencing with other sources of the literature showed enrichment of cell activation, differentiation and signaling, especially mitogen-activated protein kinase (MAPK) and Rho-GTPases pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Reanalysis of Gene Expression Profiles of CD4+ T Cells Treated with HIV-1 Latency Reversal Agents

2020

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“…To test the first hypothesis, we took advantage of findings by others describing that histone deacetylase (HDAC) inhibitors, BET protein inhibitors or cell differentiating agents, through a variety of specific and off-target effects trigger genome-wide changes to gene expression patterns, and as such create transcriptomic noise [92][93][94][95][96][97][98][99][100][101][102]. Some have actually argued that HDAC inhibitors would trigger HIV-1 reactivation by inducing an increase in genetic noise [103] and the varying potential of different histone deacetylase inhibitors to trigger HIV-1 reactivation has been linked to the induction of differential host cell responses [104].…”

Section: Gene Expression Patterns Associated With Cd3-inert Latently mentioning

confidence: 99%

Extensive proteomic and transcriptomic changes quench the TCR/CD3 activation signal of latently HIV-1 infected T cells

Carlin

Greer

Duverger

et al. 2020

Preprint

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ABSTRACTAlthough the ability of HIV-1 to reside in a latent state in CD4+ T cells constitutes a critical hurdle to a curative therapy, the biomolecular mechanisms by which latent HIV-1 infection is established and maintained are only partially understood. Ex vivo studies have shown that T cell receptor/CD3 stimulation only triggered HIV-1 reactivation in a fraction of the latently infected CD4+ T cell reservoir, suggesting that parts of the T cell population hosting latent HIV-1 infection events are altered to be TCR/CD3-activation-inert. We provide experimental evidence that HIV-1 infection of primary T cells and T cell lines indeed generates a substantial amount of TCR/CD3 activation-inert latently infected T cells. HIV-1 induced host cell TCR/CD3 inertness is thus a conserved mechanism that contributes to the stability of latent HIV-1 infection. Proteomic and genome-wide RNA-level analysis comparing CD3-responsive and CD3-inert latently HIV-1 infected T cells, followed by software-based integration of the data into protein-protein interaction networks (PINs) suggested two phenomena to govern CD3-inertness: (i) the presence of extensive transcriptomic noise that affected the efficacy of CD3 signaling and (ii) defined changes to specific signaling pathways. Validation experiments demonstrated that compounds known to increase transcriptomic noise further diminished the ability of TCR/CD3 stimulation to trigger HIV-1 reactivation. Conversely, targeting specific central nodes in the generated PINs such as STAT3 improved the ability of TCR/CD3 activation to trigger HIV-1 reactivation in T cell lines and primary T cells. The data emphasize that latent HIV-1 infection is largely the result of extensive, stable biomolecular changes to the signaling network of the host T cells harboring latent HIV-1 infection events. In extension, the data imply that therapeutic restoration of host cell TCR/CD3 responsiveness could enable gradual reservoir depletion without the need for therapeutic activators, driven by cognate antigen recognition.AUTHOR SUMMARYA curative therapy for HIV-1 infection will at least require the eradication of a small pool of CD4+ helper T cells in which the virus can persist in a latent state, even after years of successful antiretroviral therapy. It has been assumed that activation of these viral reservoir T cells will also reactivate the latent virus, which is a prerequisite for the destruction of these cells. Remarkably, this is not the case and following application of even the most potent stimuli that activate normal T cells through their T cell receptor, a large portion of the latent virus pool remains in a dormant state. Herein we demonstrate that a large part of latent HIV-1 infection events reside in T cells that have been rendered activation inert by the actual infection event. We provide a systemwide, biomolecular description of the changes that render latently HIV-1 infected T cells activation inert and using this description, devise pharmacologic interference strategies that render initially activation inert T cells responsive to stimulation. This in turn allows for efficient triggering of HIV-1 reactivation in a large part of the latently HIV-1 infected T cell reservoir.

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Characteristics and mechanisms of latency-reversing agents in the activation of the human immunodeficiency virus 1 reservoir

Zhou,

Jiang,

Zhong

et al. 2023

Arch Virol

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Histone deacetylase inhibitors induce complex host responses that contribute to differential potencies of these compounds in HIV reactivation

Cited by 23 publications

References 56 publications

Reanalysis of Gene Expression Profiles of CD4+ T Cells Treated with HIV-1 Latency Reversal Agents

Reanalysis of Gene Expression Profiles of CD4+ T Cells Treated with HIV-1 Latency Reversal Agents

Extensive proteomic and transcriptomic changes quench the TCR/CD3 activation signal of latently HIV-1 infected T cells

Characteristics and mechanisms of latency-reversing agents in the activation of the human immunodeficiency virus 1 reservoir

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