Selective Class I HDAC Inhibitors Based on Aryl Ketone Zinc Binding Induce HIV-1 Protein for Clearance

ABSTRACT Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4+ T cells is a significant contributor to the persistence of infection, allowing the virus to evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase (HDAC) inhibitors are capable of inducing expression of quiescent HIV-1 in latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine the specific HDACs that regulate HIV-1 transcription, we evaluated HDAC1 to HDAC11 RNA expression and protein expression and compartmentalization in the resting CD4+ T cells of HIV-1-positive, aviremic patients. HDAC1, -3, and -7 had the highest mRNA expression levels in these cells. Although all HDACs were detected in resting CD4+ T cells by Western blot analysis, HDAC5, -8, and -11 were primarily sequestered in the cytoplasm. Using chromatin immunoprecipitation assays, we detected HDAC1, -2, and -3 at the HIV-1 promoter in Jurkat J89GFP cells. Targeted inhibition of HDACs by small interfering RNA demonstrated that HDAC2 and HDAC3 contribute to repression of HIV-1 long terminal repeat expression in the HeLa P4/R5 cell line model of latency. Together, these results suggest that HDAC inhibitors specific for a limited number of class I HDACs may offer a targeted approach to the disruption of persistent HIV-1 infection.

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Faculty Opinions recommendation of The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.6136957.6362054 ◽

2010 ◽

Author(s):

Thomas Hope ◽

Anna Figueiredo

Keyword(s):

Hla Class I ◽

Class I ◽

Genetic Determinants ◽

Peptide Presentation ◽

Hiv 1

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Development and Validation of High-Content Analysis for Screening HDAC6-Selective Inhibitors

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/24725552211002463 ◽

2021 ◽

pp. 247255522110024

Author(s):

Yunhong Nong ◽

Yanyan Hou ◽

Yuting Pu ◽

Si Li ◽

Yan Lan

Keyword(s):

Content Analysis ◽

Adverse Effects ◽

Hdac Inhibitors ◽

Histone H3 ◽

Class I ◽

Cell Seeding ◽

Clinical Evaluations ◽

Structure Activity ◽

High Content Analysis ◽

Development And Validation

Throughout recent decades, histone deacetylase (HDAC) inhibitors have shown encouraging potential in cancer treatment, and several pan-HDAC inhibitors have been approved for treating malignant cancers. Numerous adverse effects of pan-HDAC inhibitors have been reported, however, during preclinical and clinical evaluations. To avoid undesirable responses, an increasing number of investigations are focusing on the development of isotype-selective HDAC inhibitors. In this study, we present an effective and quantitative cellular assay using high-content analysis (HCA) to determine compounds’ inhibition of the activity of HDAC6 and Class I HDAC isoforms, by detecting the acetylation of their corresponding substrates (i.e., α-tubulin and histone H3). Several conditions that are critical for HCA assays, such as cell seeding number, fixation and permeabilization reagent, and antibody dilution, have been fully validated in this study. We used selective HDAC6 inhibitors and inhibitors targeting different HDAC isoforms to optimize and validate the capability of the HCA assay. The results indicated that the HCA assay is a robust assay for quantifying compounds’ selectivity of HDAC6 and Class I HDAC isoforms in cells. Moreover, we screened a panel of compounds for HDAC6 selectivity using this HCA assay, which provided valuable information for the structure–activity relationship (SAR). In summary, our results suggest that the HCA assay is a powerful tool for screening selective HDAC6 inhibitors.

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Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes

Journal of Virology ◽

10.1128/jvi.01580-06 ◽

2006 ◽

Vol 81 (4) ◽

pp. 1619-1631 ◽

Cited By ~ 64

Author(s):

Xu G. Yu ◽

Mathias Lichterfeld ◽

Senica Chetty ◽

Katie L. Williams ◽

Stanley K. Mui ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Viral Escape ◽

Class I ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703+ individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

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High Resolution Human Leukocyte Antigen Class I Allele Frequencies and HIV-1 Infection Associations in Chinese Han and Uyghur Cohorts

PLoS ONE ◽

10.1371/journal.pone.0050656 ◽

2012 ◽

Vol 7 (12) ◽

pp. e50656

Author(s):

Yanhou Liu ◽

Zhongfang Zhao ◽

Tianyi Li ◽

Qi Liao ◽

Nicholas Kushner ◽

...

Keyword(s):

High Resolution ◽

Human Leukocyte Antigen ◽

Human Leukocyte Antigen Class ◽

Human Leukocyte ◽

Allele Frequencies ◽

Class I ◽

Chinese Han ◽

Leukocyte Antigen ◽

Hiv 1 ◽

Leukocyte Antigen Class I

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Human Immunodeficiency Virus Type 1 Replication in the Absence of Integrase-Mediated DNA Recombination: Definition of Permissive and Nonpermissive T-Cell Lines

Journal of Virology ◽

10.1128/jvi.75.17.7944-7955.2001 ◽

2001 ◽

Vol 75 (17) ◽

pp. 7944-7955 ◽

Cited By ~ 78

Author(s):

Noriko Nakajima ◽

Richard Lu ◽

Alan Engelman

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Lines ◽

Dna Recombination ◽

Cell Types ◽

Class Ii ◽

Class I ◽

Immunodeficiency Virus ◽

T Cell Lines ◽

Hiv 1

ABSTRACT Functional retroviral integrase protein is thought to be essential for productive viral replication. Yet, previous studies differed on the extent to which integrase mutant viruses expressed human immunodeficiency virus type 1 (HIV-1) genes from unintegrated DNA. Although one reason for this difference was that class II integrase mutations pleiotropically affected the viral life cycle, another reason apparently depended on the identity of the infected cell. Here, we analyzed integrase mutant viral infectivities in a variety of cell types. Single-round infectivity of class I integration-specific mutant HIV-1 ranged from <0.03 to 0.3% of that of the wild type (WT) across four different T-cell lines. Based on this approximately 10-fold influence of cell type on mutant gene expression, we examined class I and class II mutant replication kinetics in seven different cell lines and two primary cell types. Unexpectedly, some cell lines supported productive class I mutant viral replication under conditions that restricted class II mutant growth. Cells were defined as permissive, semipermissive, or nonpermissive based on their ability to support the continual passage of class I integration-defective HIV-1. Mutant infectivity in semipermissive and permissive cells as quantified by 50% tissue culture infectious doses, however, was only 0.0006 to 0.005% of that of WT. Since the frequencies of mutant DNA recombination in these lines ranged from 0.023 to <0.093% of the WT, we conclude that productive replication in the absence of integrase function most likely required the illegitimate integration of HIV-1 into host chromosomes by cellular DNA recombination enzymes.

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Faculty Opinions recommendation of TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717949368.793454529 ◽

2012 ◽

Author(s):

Andrew Badley

Keyword(s):

Protective Effect ◽

Hla Class I ◽

Class I ◽

Hla Class I Molecules ◽

Hiv 1

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Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+ T Cells

Journal of Virology ◽

10.1128/jvi.01943-16 ◽

2017 ◽

Vol 91 (16) ◽

Cited By ~ 11

Author(s):

Jean-François Bolduc ◽

Laurent Hany ◽

Corinne Barat ◽

Michel Ouellet ◽

Michel J. Tremblay

Keyword(s):

T Cells ◽

Histone Acetylation ◽

Disease Progression ◽

Histone Deacetylase ◽

Histone Deacetylases ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Class I ◽

Hdac Activity ◽

Hiv 1

ABSTRACT In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4+ T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4+ T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4+ T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4+ T cells to productive HIV-1 infection. IMPORTANCE Alterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4+ T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression.

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Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.76.16.8276-8284.2002 ◽

2002 ◽

Vol 76 (16) ◽

pp. 8276-8284 ◽

Cited By ~ 106

Author(s):

Jianming Tang ◽

Shenghui Tang ◽

Elena Lobashevsky ◽

Angela D. Myracle ◽

Ulgen Fideli ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Class I ◽

Hla Class I Molecules ◽

Immunodeficiency Virus ◽

Clade C ◽

Hiv 1

ABSTRACT The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8+ cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log10 VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log10 VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.

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