Synergistic Activation of Human Immunodeficiency Virus Type 1 Promoter Activity by NF-κB and Inhibitors of Deacetylases: Potential Perspectives for the Development of Therapeutic Strategies

ABSTRACT The transcription factor NF-κB plays a central role in the human immunodeficiency virus type 1 (HIV-1) activation pathway. HIV-1 transcription is also regulated by protein acetylation, since treatment with deacetylase inhibitors such as trichostatin A (TSA) or sodium butyrate (NaBut) markedly induces HIV-1 transcriptional activity of the long terminal repeat (LTR) promoter. Here, we demonstrate that TSA (NaBut) synergized with both ectopically expressed p50/p65 and tumor necrosis factor alpha/SF2 (TNF)-induced NF-κB to activate the LTR. This was confirmed for LTRs from subtypes A through G of the HIV-1 major group, with a positive correlation between the number of κB sites present in the LTRs and the amplitude of the TNF-TSA synergism. Mechanistically, TSA (NaBut) delayed the cytoplasmic recovery of the inhibitory protein IκBα. This coincided with a prolonged intranuclear presence and DNA binding activity of NF-κB. The physiological relevance of the TNF-TSA (NaBut) synergism was shown on HIV-1 replication in both acutely and latently HIV-infected cell lines. Therefore, our results open new therapeutic strategies aimed at decreasing or eliminating the pool of latently HIV-infected reservoirs by forcing viral expression.

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Counterregulation of Chromatin Deacetylation and Histone Deacetylase Occupancy at the Integrated Promoter of Human Immunodeficiency Virus Type 1 (HIV-1) by the HIV-1 Repressor YY1 and HIV-1 Activator Tat

Molecular and Cellular Biology ◽

10.1128/mcb.22.9.2965-2973.2002 ◽

2002 ◽

Vol 22 (9) ◽

pp. 2965-2973 ◽

Cited By ~ 165

Author(s):

Guocheng He ◽

David M. Margolis

Keyword(s):

Human Immunodeficiency Virus ◽

Histone Deacetylase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Trichostatin A ◽

Dominant Negative Mutant ◽

Histone Deacetylase 1 ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Repression of human immunodeficiency virus type 1 (HIV-1) transcription may contribute to the establishment or maintenance of proviral quiescence in infected CD4+ cells. The host factors YY1 and LSF cooperatively recruit histone deacetylase 1 (HDAC1) to the HIV-1 long terminal repeat (LTR) and inhibit transcription. We demonstrate here regulation of occupancy of HDAC1 at a positioned nucleosome (nuc 1) near the transcription start site of integrated LTR. We find that expression of YY1 increases occupancy by HDAC1, decreases acetylation at nuc 1, and downregulates LTR expression. HDAC1 recruitment and histone hypoacetylation were also seen when Tat activation was inhibited by the overexpression of YY1. A YY1 mutant without an HDAC1 interaction domain and incompetent to inhibit LTR activation fails to recruit HDAC1 to LTR or decrease nuc 1 acetylation. Further, expression of a dominant-negative mutant of LSF (dnLSF), which inhibits LSF occupancy and LTR repression, results in acetylation and decreased HDAC1 occupancy at nuc 1. Conversely, exposure of cells to the histone deacetylase inhibitor trichostatin A or activation of LTR expression by HIV-1 Tat results in the displacement of HDAC1 from nuc 1, in association with increased acetylation of histone H4. Recruitment of HDAC1 to the LTR nuc 1 can counteract Tat activation and repress LTR expression. Significantly, when repression is overcome, LTR activation is associated with decreased HDAC1 occupancy. Since the persistence of integrated HIV-1 genomes despite potent suppression of viral replication is a major obstacle for current antiretroviral therapy, strategies to selectively disrupt the quiescence of chromosomal provirus may play a role in the future treatment of AIDS.

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Characterization of Human Immunodeficiency Virus Type 1 Replication in Immature and Mature Dendritic Cells Reveals Dissociable cis- and trans-Infection

Journal of Virology ◽

10.1128/jvi.01081-07 ◽

2007 ◽

Vol 81 (20) ◽

pp. 11352-11362 ◽

Cited By ~ 67

Author(s):

Chunsheng Dong ◽

Alicia M. Janas ◽

Jian-Hua Wang ◽

Wendy J. Olson ◽

Li Wu

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Dendritic Cells ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Dendritic cells (DCs) transmit human immunodeficiency virus type 1 (HIV-1) to CD4+ T cells through the trans- and cis-infection pathways; however, little is known about the relative efficiencies of these pathways and whether they are interdependent. Here we compare cis- and trans-infections of HIV-1 mediated by immature DCs (iDCs) and mature DCs (mDCs), using replication-competent and single-cycle HIV-1. Monocyte-derived iDCs were differentiated into various types of mDCs by lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-α), and CD40 ligand (CD40L). iDCs and CD40L-induced mDCs were susceptible to HIV-1 infection and mediated efficient viral transmission to CD4+ T cells. Although HIV-1 cis-infection was partially restricted in TNF-α-induced mDCs and profoundly blocked in LPS-induced mDCs, these cells efficiently promoted HIV-1 trans-infection of CD4+ T cells. The postentry restriction of HIV-1 infection in LPS-induced mDCs was identified at the levels of reverse transcription and postintegration, using real-time PCR quantification of viral DNA and integration. Furthermore, nucleofection of DCs with HIV-1 proviral DNA confirmed that impaired gene expression of LPS-induced mDCs was responsible for the postentry restriction of HIV-1 infection. Our results suggest that various DC subsets in vivo may differentially contribute to HIV-1 dissemination via dissociable cis- and trans-infections.

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Differential Susceptibility to Human Immunodeficiency Virus Type 1 Infection of Myeloid and Plasmacytoid Dendritic Cells

Journal of Virology ◽

10.1128/jvi.79.14.8861-8869.2005 ◽

2005 ◽

Vol 79 (14) ◽

pp. 8861-8869 ◽

Cited By ~ 156

Author(s):

Anna Smed-Sörensen ◽

Karin Loré ◽

Jayanand Vasudevan ◽

Mark K. Louder ◽

Jan Andersson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Dendritic Cells ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Ex Vivo ◽

Productive Infection ◽

Necrosis Factor Alpha ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs) plays an important role in HIV-1 transmission and pathogenesis. Here, we studied the susceptibility of ex vivo-isolated CD11c+ myeloid DCs (MDCs) and CD123+ plasmacytoid DCs (PDCs) to HIV-1 infection and the function of these cells early after infection. Both DC subsets were susceptible to CCR5- and CXCR4-using HIV-1 isolates (BaL and IIIB, respectively). However, MDCs were more susceptible to HIV-1BaL infection than donor-matched PDCs. In addition, HIV-1BaL infected MDCs more efficiently than HIV-1IIIB, whereas PDCs were equally susceptible to both isolates. While exposure to HIV-1 alone resulted in only weak maturation of DCs, Toll-like receptor 7/8 ligation induced full maturation in both infected and uninfected DCs. Maturation did not increase HIV-1 replication in infected DCs, and infected DCs retained their ability to produce tumor necrosis factor alpha after stimulation. Both HIV-1 isolates induced alpha interferon production exclusively in PDCs, irrespective of productive infection. In conclusion, PDCs and MDCs were susceptible to HIV-1 infection, but neither displayed functional defects as a consequence of infection. The difference in susceptibility of PDCs and MDCs to HIV-1 may have implications for HIV-1 transmission and DC-mediated transfer of HIV-1 to T cells.

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Potent and selective inhibition of human immunodeficiency virus type 1 transcription by piperazinyloxoquinoline derivatives.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.6.1250 ◽

1997 ◽

Vol 41 (6) ◽

pp. 1250-1255 ◽

Cited By ~ 56

Author(s):

M Baba ◽

M Okamoto ◽

M Makino ◽

Y Kimura ◽

T Ikeuchi ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Immunodeficiency Virus ◽

Infected Cells ◽

K 12 ◽

Hiv 1

We have found novel piperazinyloxoquinoline derivatives to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in both acutely and chronically infected cells. 8-Difluoromethoxy-1-ethyl-6-fluoro-1,4-didehydro-7-[4-(2-met hoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12), the most potent congener of the series, completely inhibited HIV-1 replication in acutely infected MOLT-4 cells at a concentration of 0.16 to 0.8 microM without showing any cytotoxicity. The compound completely suppressed tumor necrosis factor alpha (TNF-alpha)-induced HIV-1 expression in latently infected cells (OM-10.1) and constitutive viral production in chronically infected cells (MOLT-4/III(B)) at a concentration of 0.8 microM. K-12 could also inhibit HIV-1 antigen expression in OM-10.1 and MOLT-4/III(B) cells at this concentration. Northern blot analysis revealed that K-12 selectively prevented the accumulation of HIV-1 mRNA in MOLT-4/III(B) and TNF-alpha-treated OM-10.1 cells in a dose-dependent fashion. It was not inhibitory to HIV-1 Tat or the cellular transcription factors NF-kappaB and Sp1, suggesting that the piperazinyloxoquinoline derivatives are a group of HIV-1 transcription inhibitors with a unique mechanism of action.

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