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HIV latency reactivation

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https://www.readbyqxmd.com/read/29343578/a-new-quinoline-brd4-inhibitor-targets-a-distinct-latent-hiv-1-reservoir-for-re-activation-from-other-shock-drugs
#1
Erik Abner, Mateusz Stoszko, Lei Zeng, Heng-Chang Chen, Andrea Izquierdo-Bouldstridge, Tsuyoshi Konuma, Eduard Zorita, Elisa Fanunza, Qiang Zhang, Tokameh Mahmoudi, Ming-Ming Zhou, Guillaume J Filion, Albert Jordan
Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol) that is able to reactivate viral transcription in several models of HIV latency including J-Lat cells through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or 'shock' drugs such as PKC agonists or HDAC inhibitors...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29321330/glycosyl-phosphatidylinositol-anchored-anti-hiv-env-single-chain-variable-fragments-interfere-with-hiv-1-env-processing-and-viral-infectivity
#2
Anisha Misra, Emile Gleeson, Weiming Wang, Chaobaihui Ye, Paul Zhou, Jason T Kimata
In previous studies, we demonstrated that single-chain variable fragments (scFv) from anti-HIV Env monoclonal antibodies act as entry inhibitors when tethered to the surface of target cells by a glycosyl-phosphitidylinositol (GPI) anchor. Interestingly, even if a virus escapes inhibition at entry, its replication is ultimately controlled. We hypothesized that in addition to functioning as entry inhibitors, anti-HIV GPI-scFvs may also interact with Env in an infected cell, thereby interfering with infectivity of newly produced virions...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29277280/lymphadenopathies-in-human-immunodeficiency-virus-infection
#3
REVIEW
Carlos Barrionuevo-Cornejo, Daniela Dueñas-Hancco
This article describes the various non-neoplastic lymphadenopathies that occur in patients infected with the human immunodeficiency virus (HIV), before or during the stage of acquired immunodeficiency syndrome (AIDS). The stages that develop during the HIV infection include: primary infection (acute infection, spread of the virus, development of host immune response, and acute retroviral syndrome), chronic infection or clinical latency, and finally, the AIDS stage. Non-neoplastic lymphadenopathies can occur at any of these phases of the infection and are due to multiple causes that can be divided into infectious causes (bacterial, fungal, parasitic, viral), and reactive causes (persistent generalized lymphadenopathy and a variety of situations that they also occur in immunocompetent people such as Castleman's disease and Kikuchi-Fujimoto's disease, among others)...
December 6, 2017: Seminars in Diagnostic Pathology
https://www.readbyqxmd.com/read/29246970/compounds-producing-an-effective-combinatorial-regimen-for-disruption-of-hiv-1-latency
#4
Pargol Hashemi, Kris Barreto, Wendy Bernhard, Adam Lomness, Nicolette Honson, Tom A Pfeifer, P Richard Harrigan, Ivan Sadowski
Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed "shock-and-kill" strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compounds that are capable of reversing HIV latency without affecting the general T-cell activation state. The new compounds exhibit synergy for reactivation of latent provirus with other latency-reversing agents (LRAs), in particular ingenol-3-angelate/PEP005...
December 15, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29228979/contrasting-effect-of-the-latency-reversing-agents-bryostatin-1-and-jq1-on-astrocyte-mediated-neuroinflammation-and-brain-neutrophil-invasion
#5
Alizé Proust, Corinne Barat, Mathieu Leboeuf, Jean Drouin, Michel J Tremblay
BACKGROUND: Despite effectiveness of the combined antiretroviral therapy, HIV-1 persists in long-lived latently infected cells. Consequently, new therapeutic approaches aimed at eliminating this latent reservoir are currently being developed. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed. However, the impact of LRA on the central nervous system (CNS) remains elusive. METHODS: We used human fetal astrocytes and investigated the effects of several LRA on their functional and secretory activities...
December 11, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29212213/the-bromodomain-and-extraterminal-domain-inhibitor-bromosporine-synergistically-reactivates-latent-hiv-1-in-latently-infected-cells
#6
Hanyu Pan, Panpan Lu, Yinzhong Shen, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, He Yang, Inam Ulla Khan, Muya Zhou, Bokang Li, Ziyu Zhang, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
The long-lived latent HIV-1 reservoir is the major barrier for complete cure of Acquired Immune Deficiency Syndrome (AIDS). Here we report that a novel bromodomain and extraterminal domain (BET) inhibitor bromosporine which can broadly target BETs, is able to potently reactivate HIV-1 replication in different latency models alone and more powerful when combined with prostratin or TNF-α. Furthermore, the treatment with bromosporine induced HIV-1 full-length transcripts in resting CD4+ T cells from infected individuals with suppressive antiretroviral therapy (ART) ex vivo, with no obvious cytotoxicity or global activation of T cell...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207194/quercetin-synergistically-reactivates-human-immunodeficiency-virus-type-1-latency-by-activating-nuclear-factor%C3%A2-%C3%AE%C2%BAb
#7
Xinyi Yang, Xiaoli Zhu, Haiyan Ji, Junxiao Deng, Panpan Lu, Zhengtao Jiang, Xian Li, Yibo Wang, Chuqiao Wang, Jingya Zhao, Yanan Wang, Yangcheng Zhong, He Yang, Huanzhang Zhu
Highly active antiretroviral therapy (HAART) is very effective in suppressing human immunodeficiency virus type 1 (HIV‑1) replication. However, the treatment is required to be administered for the remainder of an individual's lifetime due to latent HIV‑1 reservoirs. The 'shock‑and‑kill' strategy, which involves using agents to reactivate latent HIV‑1 and subsequently killing latently infected cells in the presence of HAART, was recently proposed. Unfortunately, no agents have currently demonstrated an ability to reactivate latent HIV‑1 in vivo in the absence of toxicity...
November 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29192235/multiplex-single-cell-visualization-of-nucleic-acids-and-protein-during-hiv-infection
#8
Maritza Puray-Chavez, Philip R Tedbury, Andrew D Huber, Obiaara B Ukah, Vincent Yapo, Dandan Liu, Juan Ji, Jennifer J Wolf, Alan N Engelman, Stefan G Sarafianos
Technical limitations in simultaneous microscopic visualization of RNA, DNA, and proteins of HIV have curtailed progress in this field. To address this need we develop a microscopy approach, multiplex immunofluorescent cell-based detection of DNA, RNA and Protein (MICDDRP), which is based on branched DNA in situ hybridization technology. MICDDRP enables simultaneous single-cell visualization of HIV (a) spliced and unspliced RNA, (b) cytoplasmic and nuclear DNA, and (c) Gag. We use MICDDRP to visualize incoming capsid cores containing RNA and/or nascent DNA and follow reverse transcription kinetics...
December 1, 2017: Nature Communications
https://www.readbyqxmd.com/read/29192216/bet-inhibitors-rvx-208-and-pfi-1-reactivate-hiv-1-from-latency
#9
Panpan Lu, Yinzhong Shen, He Yang, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, Hanyu Pan, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29170390/systems-analysis-of-latent-hiv-reversal-reveals-altered-stress-kinase-signaling-and-increased-cell-death-in-infected-t-cells
#10
Linda E Fong, Endah S Sulistijo, Kathryn Miller-Jensen
Viral latency remains the most significant obstacle to HIV eradication. Clinical strategies aim to purge the latent CD4+ T cell reservoir by activating viral expression to induce death, but are undercut by the inability to target latently infected cells. Here we explored the acute signaling response of latent HIV-infected CD4+ T cells to identify dynamic phosphorylation signatures that could be targeted for therapy. Stimulation with CD3/CD28, PMA/ionomycin, or latency reversing agents prostratin and SAHA, yielded increased phosphorylation of IκBα, ERK, p38, and JNK in HIV-infected cells across two in vitro latency models...
November 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29142313/effects-of-exosome-on-the-activation-of-cd4-t-cells-in-rhesus-macaques-a-potential-application-for-hiv-latency-reactivation
#11
Xiaowu Hong, Blake Schouest, Huanbin Xu
Exosomes are small extracellular vesicles (EVs), released by a wide variety of cell types, carry donor origin-proteins, cytokines, and nucleic acids, transport these cargos to adjacent or distant specific recipient cells, and thereby regulate gene expression and activation of target cells. In this study, we isolated and identified exosomes in rhesus macaques, and investigated their effects on cell tropism and activation, especially their potential to reactivate HIV latency. The results indicated that plasma-derived exosomes preferentially fuse to TCR-activated T cells and autologous parent cells...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29135580/wake-me-up-before-you-go-a-strategy-to-reduce-the-latent-hiv-reservoir
#12
Nicolas Chomont, Afam A Okoye, David Favre, Lydie Trautmann
: In the quest to eliminate or reduce the HIV reservoir, shock and kill strategies require the combined administration of a latency reversing agent (LRA) to reactivate the latent reservoir and an intervention to boost effector functions to clear this reservoir. Both parts of this strategy are quite inefficient when LRAs are administered to HIV-infected individuals on suppressive ART for several years, possibly due to low levels of induced antigen expression, negative impact of LRAs on clearance mechanisms, and very low number of effective cytotoxic T cells (CTLs)...
November 10, 2017: AIDS
https://www.readbyqxmd.com/read/29118123/estimating-initial-viral-levels-during-hiv-siv-reactivation-from-latency
#13
Mykola Pinkevych, Christine M Fennessey, Deborah Cromer, Martin Tolstrup, Ole S Søgaard, Thomas A Rasmussen, Brandon F Keele, Miles P Davenport
HIV viremia rebounds rapidly after treatment interruption, and a variety of strategies are being explored to reduce or control viral reactivation post-treatment. This viral rebound arises from reactivation of individual latently infected cells, which spread during ongoing rounds of productive infection. The level of virus produced by the initial individual reactivating cells is not known, although it may have major implications for the ability of different immune interventions to control viral rebound. Here we use data from both HIV and SIV treatment interruption studies to estimate the initial viral load post-interruption and thereby the initial individual reactivation event...
November 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29099677/novel-latency-reversal-agents-for-hiv-1-cure
#14
Adam M Spivak, Vicente Planelles
Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness; however, ART is not curative owing to the persistence of replication-competent, latent proviruses in long-lived restingTcells. Strategies that target these latently infected cells and allow immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir so that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure...
November 3, 2017: Annual Review of Medicine
https://www.readbyqxmd.com/read/29089933/curaxin-cbl0100-blocks-hiv-1-replication-and-reactivation-through-inhibition-of-viral-transcriptional-elongation
#15
Maxime J Jean, Tsuyoshi Hayashi, Huachao Huang, Justin Brennan, Sydney Simpson, Andrei Purmal, Katerina Gurova, Michael C Keefer, James J Kobie, Netty G Santoso, Jian Zhu
Despite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurprisingly, efforts for a sterilizing cure have focused on the "shock and kill" strategy using latency-reversing agents (LRAs) to complement cART in order to eliminate these latent reservoirs. However, this method faces numerous challenges...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29071475/assays-to-measure-latency-reservoirs-and-reactivation
#16
Janet D Siliciano, Robert F Siliciano
HIV-1 persists even in patients who are successfully treated with combination antiretroviral therapy. The major barrier to cure is a small pool of latently infected resting CD4(+) T cells carrying an integrated copy of the viral genome that is not expressed while the cells remain in a resting state. Targeting this latent reservoir is a major focus of HIV-1 cure research, and the development of a rapid and scalable assay for the reservoir is a rate-limiting step in the search for a cure. The most commonly used assays are standard PCR assays targeting conserved regions of the HIV-1 genome...
October 26, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/29046460/myeloid-dendritic-cells-repress-human-cytomegalovirus-gene-expression-and-spread-by-releasing-interferon-unrelated-soluble-antiviral-factors
#17
Bahram Kasmapour, Tobias Kubsch, Ulfert Rand, Britta Eiz-Vesper, Martin Messerle, Florian W R Vondran, Bettina Wiegmann, Axel Haverich, Luka Cicin-Sain
Cytomegalovirus (CMV) is a beta-herpesvirus that latently infects most adult humans worldwide and is a major cause of morbidity and mortality in immunocompromised hosts. Latent human CMV (HCMV) is believed to reside in precursors of myeloid-lineage, leukocytes and monocytes, which give raise to macrophages and dendritic cells. We report here that human monocyte derived DCs (mo-DC) suppress HCMV infection in coculture with infected fibroblasts target cells in an effector-to-target-ratio dependent manner. Intriguingly, optimal activation of mo-DC was achieved in coculture conditions, not by their direct infection with HCMV, implying that mo-DC may recognize unique molecular patterns on, or within, infected fibroblasts...
October 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29027985/triterpenoids-from-ocimum-labiatum-activates-latent-hiv-1-expression-in-vitro-potential-for-use-in-adjuvant-therapy
#18
Petrina Kapewangolo, Justin J Omolo, Pascaline Fonteh, Martha Kandawa-Schulz, Debra Meyer
Latent HIV reservoirs in infected individuals prevent current treatment from eradicating infection. Treatment strategies against latency involve adjuvants for viral reactivation which exposes viral particles to antiretroviral drugs. In this study, the effect of novel triterpenoids isolated from Ocimum labiatum on HIV-1 expression was measured through HIV-1 p24 antigen capture in the U1 latency model of HIV-1 infection and in peripheral blood mononuclear cells (PBMCs) of infected patients on combination antiretroviral therapy (cART)...
October 13, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29021396/quiescence-promotes-latent-hiv-infection-and-resistance-to-reactivation-from-latency-with-histone-deacetylase-inhibitors
#19
Mark M Painter, Thomas D Zaikos, Kathleen L Collins
Human immunodeficiency virus type-1 (HIV-1) establishes transcriptionally silent latent infections in many cell types, including resting memory T cells and hematopoietic stem and progenitor cells (HSPCs), which allow the virus to persist in infected individuals despite antiretroviral therapy. Developing in vitro models of HIV-1 latency that recapitulate the characteristics of latently-infected cells in vivo is crucial to identifying and developing effective latency-reversing therapies. HSPCs exist in a quiescent state in vivo, and quiescence is correlated with latent infections in T cells...
October 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28949981/mycobacterium-tuberculosis-reactivates-latent-hiv-1-in-t-cells-in-vitro
#20
Erica C Larson, Camille L Novis, Laura J Martins, Amanda B Macedo, Kadyn E Kimball, Alberto Bosque, Vicente Planelles, Louis R Barrows
Following proviral integration into the host cell genome and establishment of a latent state, the human immunodeficiency virus type 1 (HIV-1) can reenter a productive life cycle in response to various stimuli. HIV-1 reactivation occurs when transcription factors, such as nuclear factor-κB (NF-κB), nuclear factor of activated T cells (NFAT), and activator protein -1 (AP-1), bind cognate sites within the long terminal repeat (LTR) region of the HIV-1 provirus to promote transcription. Interestingly, pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) can reactivate latent HIV-1 through activation of the transcription factor NF-κB...
2017: PloS One
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