scholarly journals Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

2020 ◽  
Author(s):  
Amina Ait Ammar ◽  
Maxime Bellefroid ◽  
Fadoua Daouad ◽  
Valérie Martinelli ◽  
Jeanne Van Assche ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Microglial Cells ◽  
Viral Gene ◽  
Cellular Transcription Factor ◽  
Current Therapies ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACTHIV-1 latency generates reservoirs that prevent viral eradication by the current therapies. To find strategies toward an HIV cure, detailed understandings of the molecular mechanisms underlying establishment and persistence of the reservoirs are needed. The cellular transcription factor KAP1 is known as a potent repressor of gene transcription. Here we report that KAP1 represses HIV-1 gene expression in myeloid cells including microglial cells, the major reservoir of the central nervous system. Mechanistically, KAP1 interacts and colocalizes with the viral transactivator Tat to promote its degradation via the proteasome pathway and repress HIV-1 gene expression. In myeloid models of latent HIV-1 infection, the depletion of KAP1 increased viral gene elongation and reactivated HIV-1 expression. Bound to the latent HIV-1 promoter, KAP1 associates and cooperates with CTIP2, a key epigenetic silencer of HIV-1 expression in microglial cells. In addition, Tat and CTIP2 compete for KAP1 binding suggesting a dynamic modulation of the KAP1 cellular partners upon HIV-1 infection. Altogether, our results suggest that KAP1 contributes to the establishment and the persistence of HIV-1 latency in myeloid cells.

scholarly journals Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amina Ait-Ammar ◽  
Maxime Bellefroid ◽  
Fadoua Daouad ◽  
Valérie Martinelli ◽  
Jeanne Van Assche ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Microglial Cells ◽  
Viral Gene ◽  
Cellular Transcription Factor ◽  
Current Therapies ◽  
Latent Hiv ◽  
Hiv 1

AbstractHIV-1 latency generates reservoirs that prevent viral eradication by the current therapies. To find strategies toward an HIV cure, detailed understandings of the molecular mechanisms underlying establishment and persistence of the reservoirs are needed. The cellular transcription factor KAP1 is known as a potent repressor of gene transcription. Here we report that KAP1 represses HIV-1 gene expression in myeloid cells including microglial cells, the major reservoir of the central nervous system. Mechanistically, KAP1 interacts and colocalizes with the viral transactivator Tat to promote its degradation via the proteasome pathway and repress HIV-1 gene expression. In myeloid models of latent HIV-1 infection, the depletion of KAP1 increased viral gene elongation and reactivated HIV-1 expression. Bound to the latent HIV-1 promoter, KAP1 associates and cooperates with CTIP2, a key epigenetic silencer of HIV-1 expression in microglial cells. In addition, Tat and CTIP2 compete for KAP1 binding suggesting a dynamic modulation of the KAP1 cellular partners upon HIV-1 infection. Altogether, our results suggest that KAP1 contributes to the establishment and the persistence of HIV-1 latency in myeloid cells.

scholarly journals The Current Status of Latency Reversing Agents for HIV-1 Remission

2021 ◽  
Vol 8 (1) ◽  
pp. 491-514
Author(s):  
Anthony Rodari ◽  
Gilles Darcis ◽  
Carine M. Van Lint
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Viral Gene Expression ◽  
Current Status ◽  
Viral Gene ◽  
Latently Infected ◽  
Hiv 1 ◽  
Reversing Agents

Combinatory antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 (HIV-1) replication but is not curative because cART interruption almost invariably leads to a rapid rebound of viremia due to the persistence of stable HIV-1-infected cellular reservoirs. These reservoirs are mainly composed of CD4+ T cells harboring replication-competent latent proviruses. A broadly explored approach to reduce the HIV-1 reservoir size, the shock and kill strategy, consists of reactivating HIV-1 gene expression from the latently infected cellular reservoirs (the shock), followed by killing of the virus-producing infected cells (the kill). Based on improved understanding of the multiple molecular mechanisms controlling HIV-1 latency, distinct classes of latency reversing agents (LRAs) have been studied for their efficiency to reactivate viral gene expression in in vitro and ex vivo cell models. Here, we provide an up-to-date review of these different mechanistic classes of LRAs and discuss optimizations of the shock strategy by combining several LRAs simultaneously or sequentially.

scholarly journals Hit-and-Run Stimulation: a Novel Concept To Reactivate Latent HIV-1 Infection without Cytokine Gene Induction

2010 ◽  
Vol 84 (17) ◽  
pp. 8712-8720 ◽  
Author(s):  
Frank Wolschendorf ◽  
Alexandra Duverger ◽  
Jennifer Jones ◽  
Frederic H. Wagner ◽  
Jason Huff ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Gene Induction ◽  
Cytokine Gene Expression ◽  
Latent Reservoir ◽  
Viral Gene ◽  
Cytokine Gene ◽  
Treatment Interruptions ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT Current antiretroviral therapy (ART) efficiently controls HIV-1 replication but fails to eradicate the virus. Even after years of successful ART, HIV-1 can conceal itself in a latent state in long-lived CD4+ memory T cells. From this latent reservoir, HIV-1 rebounds during treatment interruptions. Attempts to therapeutically eradicate this viral reservoir have yielded disappointing results. A major problem with previously utilized activating agents is that at the concentrations required for efficient HIV-1 reactivation, these stimuli trigger high-level cytokine gene expression (hypercytokinemia). Therapeutically relevant HIV-1-reactivating agents will have to trigger HIV-1 reactivation without the induction of cytokine expression. We present here a proof-of-principle study showing that this is a possibility. In a high-throughput screening effort, we identified an HIV-1-reactivating protein factor (HRF) secreted by the nonpathogenic bacterium Massilia timonae. In primary T cells and T-cell lines, HRF triggered a high but nonsustained peak of nuclear factor kappa B (NF-κB) activity. While this short NF-κB peak potently reactivated latent HIV-1 infection, it failed to induce gene expression of several proinflammatory NF-κB-dependent cellular genes, such as those for tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8), and gamma interferon (IFN-γ). Dissociation of cellular and viral gene induction was achievable, as minimum amounts of Tat protein, synthesized following application of a short NF-κB pulse, triggered HIV-1 transactivation and subsequent self-perpetuated HIV-1 expression. In the absence of such a positive feedback mechanism, cellular gene expression was not sustained, suggesting that strategies modulating the NF-κB activity profile could be used to selectively trigger HIV-1 reactivation.

scholarly journals Fourth NF-κB site in HIV-1 subtype-C LTR confers functional advantage to viral gene expression

Retrovirology ◽  
2009 ◽  
Vol 6 (S2) ◽  
Author(s):  
Mahesh Bachu ◽  
Rajesh V Murali ◽  
Anil MHKH Babu ◽  
Venkat SRK Yedavalli ◽  
Kuan-Teh Jeang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Subtype C ◽  
Functional Advantage ◽  
Hiv 1

scholarly journals Tax induces the recruitment of NF-kB to unintegrated HIV-1 DNA to rescue viral gene expression and replication

2021 ◽  
Author(s):  
Ishak D. Irwan ◽  
Bryan R. Cullen
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Lentiviral Vectors ◽  
Expression Vectors ◽  
Viral Gene ◽  
Epigenetic Marks ◽  
Tax Protein ◽  
Human T Cell ◽  
Activation Of Transcription ◽  
Hiv 1

AbstractWe have previously reported that the normally essential step of integration of the HIV-1 proviral DNA intermediate into the host cell genome becomes dispensable in T cells that express the Human T cell leukemia virus 1 (HTLV-1) Tax protein. The rescue of integrase (IN) deficient HIV-1 replication by Tax results from the strong activation of transcription from the long terminal repeat (LTR) promoter on episomal HIV-1 DNA, an effect that is closely correlated with the recruitment of activating epigenetic marks, such as H3Ac, and depletion of repressive epigenetic marks, such as H3K9me3, from chromatinized unintegrated proviruses. In addition, activation of transcription from unintegrated HIV-1 DNA coincides with the recruitment of NF-kB to the two NF-kB binding sites found in the HIV-1 LTR enhancer. Here we report that the recruitment of NF-kB to unintegrated viral DNA precedes, and is a prerequisite for, Tax-induced changes in epigenetic marks, so that an IN-HIV-1 mutant lacking both LTR NF-kB sites is entirely non-responsive to Tax and fails to undergo the epigenetic changes listed above. We also report that heterologous promoters introduced into IN-HIV-1-based vectors are transcriptionally active even in the absence of Tax. Finally, we failed to reproduce a recent report arguing that heterologous promoters introduced into IN-vectors based on HIV-1 are more active if the HIV-1 promoter and enhancer, located in the LTR U3 region, are deleted, in a so-called self inactivating or SIN lentivector design.ImportanceIntegrase-deficient expression vectors based on HIV-1 are becoming increasingly popular as tools for gene therapy in vivo due to their inability to cause insertional mutagenesis. However, many IN-lentiviral vectors are able to achieve only low levels of gene expression and methods to increase this low level have not been extensively explored. Here we analyze how the HTLV-1 Tax protein is able to rescue the replication of IN-HIV-1 in T cells and describe IN-lentiviral vectors that are able to express a heterologous gene effectively.

scholarly journals Impact of Tat Genetic Variation on HIV-1 Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Luna Li ◽  
Satinder Dahiya ◽  
Sandhya Kortagere ◽  
Benjamas Aiamkitsumrit ◽  
David Cunningham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcriptional Activation ◽  
Viral Gene Expression ◽  
Functional Domains ◽  
Viral Gene ◽  
Molecular Architecture ◽  
Viral Transactivator ◽  
Hiv Drugs ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation withintatof different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability withintatmay impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.

Epigenetic reprogramming of host and viral genes by Human Cytomegalovirus infection in Kasumi-3 myeloid progenitor cells at early times post-infection

2021 ◽  
Author(s):  
Eleonora Forte ◽  
Fatma Ayaloglu Butun ◽  
Christian Marinaccio ◽  
Matthew J. Schipma ◽  
Andrea Piunti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Post Infection ◽  
De Novo ◽  
Critical Role ◽  
Myeloid Cells ◽  
Viral Gene Expression ◽  
Chromatin Accessibility ◽  
Viral Gene ◽  
Dynamic Changes ◽  
Pol Ii

HCMV establishes latency in myeloid cells. Using the Kasumi-3 latency model, we previously showed that lytic gene expression is activated prior to establishment of latency in these cells. The early events in infection may have a critical role in shaping establishment of latency. Here, we have used an integrative multi-omics approach to investigate dynamic changes in host and HCMV gene expression and epigenomes at early times post infection. Our results show dynamic changes in viral gene expression and viral chromatin. Analyses of Pol II, H3K27Ac and H3K27me3 occupancy of the viral genome showed that 1) Pol II occupancy was highest at the MIEP at 4 hours post infection. However, it was observed throughout the genome; 2) At 24 hours, H3K27Ac was localized to the major immediate early promoter/enhancer and to a possible second enhancer in the origin of replication OriLyt; 3) viral chromatin was broadly accessible at 24 hpi. In addition, although HCMV infection activated expression of some host genes, we observed an overall loss of de novo transcription. This was associated with loss of promoter-proximal Pol II and H3K27Ac, but not with changes in chromatin accessibility or a switch in modification of H3K27. Importance. HCMV is an important human pathogen in immunocompromised hosts and developing fetuses. Current anti-viral therapies are limited by toxicity and emergence of resistant strains. Our studies highlight emerging concepts that challenge current paradigms of regulation of HCMV gene expression in myeloid cells. In addition, our studies show that HCMV has a profound effect on de novo transcription and the cellular epigenome. These results may have implications for mechanisms of viral pathogenesis.

scholarly journals 8 Implication of the HIV-1 pol gene intragenic enhancer in myeloid-specific viral gene expression

2017 ◽  
Vol 3 ◽  
pp. 8
Author(s):  
R. Verdikt ◽  
L. Colin ◽  
C. Vanhulle ◽  
B. Van Driessche ◽  
A. Kula ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Hiv 1

scholarly journals Evidence for Gene Expression by Unintegrated Human Immunodeficiency Virus Type 1 DNA Species

2004 ◽  
Vol 78 (20) ◽  
pp. 11263-11271 ◽  
Author(s):  
Audrey Brussel ◽  
Pierre Sonigo
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Gene ◽  
Viral Expression ◽  
Molecular Stability ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The integrated form of human immunodeficiency virus type 1 (HIV-1) DNA is classically considered to be the sole template for viral gene expression. However, several studies have suggested that unintegrated viral DNA species could also support transcription. To determine the contribution of the different species of HIV-1 DNA to viral expression, we first monitored intracellular levels of various HIV-1 DNA and RNA species in a single-round infection assay. We observed that, in comparison to the precocity of HIV-1 DNA synthesis, viral expression was delayed, suggesting that only the HIV-1 DNA species that persist for a sufficient period of time would be transcribed efficiently. We next evaluated the transcriptional activity of the circular forms of HIV-1 DNA bearing two long terminal repeats, since these episomes were reported to exhibit an intrinsic molecular stability. Our results support the notion that these circular species of HIV-1 DNA are naturally transcribed during HIV-1 infection, thereby participating in virus replication.

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