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HIV latency reactivation

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https://www.readbyqxmd.com/read/28727807/digoxin-reveals-a-functional-connection-between-hiv-1-integration-preference-and-t-cell-activation
#1
Alexander Zhyvoloup, Anat Melamed, Ian Anderson, Delphine Planas, Chen-Hsuin Lee, Janos Kriston-Vizi, Robin Ketteler, Andy Merritt, Jean-Pierre Routy, Petronela Ancuta, Charles R M Bangham, Ariberto Fassati
HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28715973/the-molecular-basis-for-human-immunodeficiency-virus-latency
#2
Uri Mbonye, Jonathan Karn
Although potent combination antiretroviral therapy can effectively block viral replication in the host, human immunodeficiency virus (HIV) persists due to the existence of latent but replication-competent proviruses residing primarily in a very small population of resting memory CD4(+) T cells. Viral latency is established when the expression of the autoregulatory viral trans-activating factor Tat is reduced to subthreshold levels. The absence of Tat reduces HIV transcription and protein production to levels that make the host cell invisible to the immune system and refractory to antiretroviral treatment...
July 17, 2017: Annual Review of Virology
https://www.readbyqxmd.com/read/28699853/foxo4-negatively-controls-tat-mediated-hiv-1-transcription-through-the-post-transcriptional-suppression-of-tat-encoding-mrna
#3
Alexandra Oteiza, Nadir Mechti
The connection between the repression of human immunodeficiency virus type 1(HIV-1) transcription and the resting CD4+ T cell state suggests that the host transcription factors involved in the active maintenance of lymphocyte quiescence are likely to repress the viral transactivator, Tat, thereby restricting HIV-1 transcription. In this study, we analysed the interplay between Tat and the forkhead box transcription factors, FoxO1 and FoxO4. We show that FoxO1 and FoxO4 antagonize Tat-mediated transactivation of HIV-1 promoter through the repression of Tat protein expression...
July 12, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28698276/a-novel-single-cell-fish-flow-assay-identifies-effector-memory-cd4-t-cells-as-a-major-niche-for-hiv-1-transcription-in-hiv-infected-patients
#4
Judith Grau-Expósito, Carla Serra-Peinado, Lucia Miguel, Jordi Navarro, Adrià Curran, Joaquin Burgos, Imma Ocaña, Esteban Ribera, Ariadna Torrella, Bibiana Planas, Rosa Badía, Josep Castellví, Vicenç Falcó, Manuel Crespo, Maria J Buzon
Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" in HIV-infected individuals. However, important technical limitations have precluded the characterization of this specific viral reservoir during both treated and untreated HIV-1 infections. Here, we used a novel single-cell RNA fluorescence in situ hybridization-flow cytometry (FISH-flow) assay that requires only 15 million unfractionated peripheral blood mononuclear cells (PBMCs) to characterize the specific cell subpopulations that transcribe HIV RNA in different subsets of CD4(+) T cells...
July 11, 2017: MBio
https://www.readbyqxmd.com/read/28689087/the-histone-deacetylase-inhibitor-saha-simultaneously-reactivates-hiv-1-from-latency-and-up-regulates-nkg2d-ligands-sensitizing-for-natural-killer-cell-cytotoxicity
#5
Maria Giovanna Desimio, Erica Giuliani, Margherita Doria
In pilot HIV-1 eradication studies, patients' immune responses were ineffective at killing viral reservoirs reactivated through latency reversing agents (LRAs) like suberoylanilide hydroxamic acid (SAHA). We hypothesized that T cells harboring reactivated HIV-1 express MIC and ULBP ligands for the activating NKG2D receptor of natural killer (NK) cells. Here, we demonstrated that MICA/B and ULBP2 are induced by SAHA on primary T cells harboring reactivated virus. Using latently HIV-1-infected J-Lat 6.3/8.4/9...
July 6, 2017: Virology
https://www.readbyqxmd.com/read/28687465/on-the-way-to-find-a-cure-purging-latent-hiv-1-reservoirs
#6
REVIEW
Christian Schwartz, Sophie Bouchat, Céline Marban, Virginie Gautier, Carine Van Lint, Olivier Rohr, Valentin Le Douce
Introduction of cART in 1996 has drastically increased the life expectancy of people living with HIV-1. However, this treatment has not allowed cure as cessation of cART is associated with a rapid viral rebound. The main barrier to the eradication of the virus is related to the persistence of latent HIV reservoirs. Evidence is now accumulating that purging the HIV-1 reservoir might lead to a cure or a remission. The most studied strategy is the so called "shock and kill" therapy. This strategy is based on reactivation of dormant viruses from the latently-infected reservoirs (the shock) followed by the eradication of the reservoirs (the kill)...
July 4, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28677507/the-hiv-1-tat-protein-mechanism-of-action-and-target-for-hiv-1-cure-strategies
#7
Andrew P Rice
The general mechanism involved in Tat activation of RNA Polymerase II (RNAP II) elongation of the integrated HIV-1 was elucidated over 20 years ago. This mechanism involves Tat binding to the TAR RNA element that forms at the 5' end of viral transcripts and recruiting a general RNAP II elongation factor termed as P-TEFb. This elongation factor consists of CDK9 and Cyclin T1, and when recruited by Tat to TAR RNA, CDK9 was proposed to phosphorylate the carboxyl terminal domain of RNAP II and thereby activate elongation...
July 4, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28673572/elimination-of-cancer-stem-cells-and-reactivation-of-latent-hiv-1-via-ampk-activation-common-mechanism-of-action-linking-inhibition-of-tumorigenesis-and-the-potential-eradication-of-hiv-1
#8
Jahahreeh Finley
Although promising treatments are currently in development to slow disease progression and increase patient survival, cancer remains the second leading cause of death in the United States. Cancer treatment modalities commonly include chemoradiation and therapies that target components of aberrantly activated signaling pathways. However, treatment resistance is a common occurrence and recent evidence indicates that the existence of cancer stem cells (CSCs) may underlie the limited efficacy and inability of current treatments to effectuate a cure...
July 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28658263/identification-of-benzazole-compounds-that-induce-hiv-1-transcription
#9
Jason D Graci, Daniel Michaels, Guangming Chen, Gillian M Schiralli Lester, Sarah Nodder, Marla Weetall, Gary M Karp, Zhengxian Gu, Joseph M Colacino, Andrew J Henderson
Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed "shock and kill"...
2017: PloS One
https://www.readbyqxmd.com/read/28638377/a-novel-bromodomain-inhibitor-reverses-hiv-1-latency-through-specific-binding-with-brd4-to-promote-tat-and-p-tefb-association
#10
Huachao Huang, Shuai Liu, Maxime Jean, Sydney Simpson, He Huang, Mark Merkley, Tsuyoshi Hayashi, Weili Kong, Irene Rodríguez-Sánchez, Xiaofeng Zhang, Hailemichael O Yosief, Hongyu Miao, Jianwen Que, James J Kobie, James Bradner, Netty G Santoso, Wei Zhang, Jian Zhu
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28637181/crosstalk-between-histone-modifications-indicates-that-inhibition-of-arginine-methyltransferase-carm1-activity-reverses-hiv-latency
#11
Zheng Zhang, Bryan C Nikolai, Leah A Gates, Sung Yun Jung, Edward B Siwak, Bin He, Andrew P Rice, Bert W O'Malley, Qin Feng
In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription...
June 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28628632/increasing-procaspase-8-expression-using-repurposed-drugs-to-induce-hiv-infected-cell-death-in-ex-vivo-patient-cells
#12
Rahul Sampath, Nathan W Cummins, Sekar Natesampillai, Gary D Bren, Thomas D Chung, Jason Baker, Keith Henry, Amélie Pagliuzza, Andrew D Badley
HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8...
2017: PloS One
https://www.readbyqxmd.com/read/28539614/the-ccr5-antagonist-maraviroc-reverses-hiv-1-latency-in-vitro-alone-or-in-combination-with-the-pkc-agonist-bryostatin-1
#13
María Rosa López-Huertas, Laura Jiménez-Tormo, Nadia Madrid-Elena, Carolina Gutiérrez, Sara Rodríguez-Mora, Mayte Coiras, José Alcamí, Santiago Moreno
A potential strategy to cure HIV-1 infection is to use latency reversing agents (LRAs) to eliminate latent reservoirs established in resting CD4+ T (rCD4+) cells. As no drug has been shown to be completely effective, finding new drugs and combinations are of increasing importance. We studied the effect of Maraviroc (MVC), a CCR5 antagonist that activates NF-κB, on HIV-1 replication from latency. HIV-1-latency models based on CCL19 or IL7 treatment, before HIV-1 infection were used. Latently infected primary rCD4+ or central memory T cells were stimulated with MVC alone or in combination with Bryostatin-1, a PKC agonist known to reverse HIV-1 latency...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28539449/anti-hiv-1-adcc-antibodies-following-latency-reversal-and-treatment-interruption
#14
Wen Shi Lee, Anne B Kristensen, Thomas A Rasmussen, Martin Tolstrup, Lars Østergaard, Ole S Søgaard, Bruce D Wines, P Mark Hogarth, Arnold Reynaldi, Miles P Davenport, Sean Emery, Janaki Amin, David A Cooper, Virginia L Kan, Julie Fox, Henning Gruell, Matthew S Parsons, Stephen J Kent
There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRA) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28529033/high-throughput-characterization-of-hiv-1-reservoir-reactivation-using-a-single-cell-in-droplet-pcr-assay
#15
Robert W Yucha, Kristen S Hobbs, Emily Hanhauser, Louise E Hogan, Wildaliz Nieves, Mehmet O Ozen, Fatih Inci, Vanessa York, Erica A Gibson, Cassandra Thanh, Hadi Shafiee, Rami El Assal, Maja Kiselinova, Yvonne P Robles, Helen Bae, Kaitlyn S Leadabrand, ShuQi Wang, Steven G Deeks, Daniel R Kuritzkes, Utkan Demirci, Timothy J Henrich
Reactivation of latent viral reservoirs is on the forefront of HIV-1 eradication research. However, it is unknown if latency reversing agents (LRAs) increase the level of viral transcription from cells producing HIV RNA or harboring transcriptionally-inactive (latent) infection. We therefore developed a microfluidic single-cell-in-droplet (scd)PCR assay to directly measure the number of CD4(+) T cells that produce unspliced (us)RNA and multiply spliced (ms)RNA following ex vivo latency reversal with either an histone deacetylase inhibitor (romidepsin) or T cell receptor (TCR) stimulation...
June 2017: EBioMedicine
https://www.readbyqxmd.com/read/28494238/smyd2-mediated-histone-methylation-contributes-to-hiv-1-latency
#16
Daniela Boehm, Mark Jeng, Gregory Camus, Andrea Gramatica, Roland Schwarzer, Jeffrey R Johnson, Philip A Hull, Mauricio Montano, Naoki Sakane, Sara Pagans, Robert Godin, Steven G Deeks, Nevan J Krogan, Warner C Greene, Melanie Ott
Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4(+) T cells...
May 10, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28472156/genetically-barcoded-siv-facilitates-enumeration-of-rebound-variants-and-estimation-of-reactivation-rates-in-nonhuman-primates-following-interruption-of-suppressive-antiretroviral-therapy
#17
Christine M Fennessey, Mykola Pinkevych, Taina T Immonen, Arnold Reynaldi, Vanessa Venturi, Priyanka Nadella, Carolyn Reid, Laura Newman, Leslie Lipkey, Kelli Oswald, William J Bosche, Matthew T Trivett, Claes Ohlen, David E Ott, Jacob D Estes, Gregory Q Del Prete, Jeffrey D Lifson, Miles P Davenport, Brandon F Keele
HIV and SIV infection dynamics are commonly investigated by measuring plasma viral loads. However, this total viral load value represents the sum of many individual infection events, which are difficult to independently track using conventional sequencing approaches. To overcome this challenge, we generated a genetically tagged virus stock (SIVmac239M) with a 34-base genetic barcode inserted between the vpx and vpr accessory genes of the infectious molecular clone SIVmac239. Next-generation sequencing of the virus stock identified at least 9,336 individual barcodes, or clonotypes, with an average genetic distance of 7 bases between any two barcodes...
May 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28471170/resveratrol-reactivates-latent-hiv-through-increasing-histone-acetylation-and-activating-heat-shock-factor-1
#18
Xiaoyun Zeng, Xiaoyan Pan, Xinfeng Xu, Jian Lin, Fuchang Que, Yuanxin Tian, Lin Li, Shuwen Liu
The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC)...
June 7, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28467486/the-effect-of-ingenol-b-on-the-suppressive-capacity-of-elite-suppressor-hiv-specific-cd8-t-cells
#19
Abena K Kwaa, Kennedy Goldsborough, Victoria E Walker-Sperling, Luiz F Pianowski, Lucio Gama, Joel N Blankson
BACKGROUND: Some latency-reversing agents (LRAs) inhibit HIV-specific CD8+ T cell responses. In a prior study of protein kinase C (PKC) agonists, we found that bryostatin-1 inhibited elite controller/suppressor (ES) CD8+ T cell suppressive activity whereas prostratin had no effect. Ingenol-B is another PKC agonist with potent LRA activity both by itself and in combination with the bromodomain inhibitor JQ1; however its effect on CD8+ T cell mediated control of HIV-1 replication is unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28465838/a-critical-review-of-the-evidence-concerning-the-hiv-latency-reversing-effect-of-disulfiram-the-possible-explanations-for-its-inability-to-reduce-the-size-of-the-latent-reservoir-in-vivo-and-the-caveats-associated-with-its-use-in-practice
#20
REVIEW
Harry D J Knights
Combination antiretroviral therapy (cART) effectively suppresses the replication of human immunodeficiency virus type 1 (HIV-1), improves immune function, and decreases the morbidity of acquired immune deficiency syndrome (AIDS). However, it is unable to eradicate the virus because it does not eliminate latently infected cells. The latent reservoir poses the major barrier to an HIV-1 cure. The "shock and kill" strategy aims to reactivate the virus and destroy latently infected cells. Many latency reversing agents (LRAs) reactivate HIV in vitro, but the absence of damaging side-effects and efficacy in vivo make disulfiram particularly promising...
2017: AIDS Research and Treatment
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