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https://www.readbyqxmd.com/read/28542329/novel-agoshrna-molecules-for-silencing-of-the-ccr5-co-receptor-for-hiv-1-infection
#1
Elena Herrera-Carrillo, Ben Berkhout
Allogeneic transplantation of blood stem cells from a CCR5-Δ32 homozygous donor to an HIV-infected individual, the "Berlin patient", led to a cure. Since then there has been a search for approaches that mimic this intervention in a gene therapy setting. RNA interference (RNAi) has evolved as a powerful tool to regulate gene expression in a sequence-specific manner and can be used to inactivate the CCR5 mRNA. Short hairpin RNA (shRNA) molecules can impair CCR5 expression, but these molecules may cause unintended side effects and they will not be processed in cells that lack Dicer, such as monocytes...
2017: PloS One
https://www.readbyqxmd.com/read/28534887/when-is-early-antiretroviral-therapy-early-enough-for-hiv-remission
#2
Eva Poveda, Manuelo Cresp
Several strategies to reduce and control the HIV reservoir are being evaluating to achieve the great challenge of HIV remission or functional cure. Some of these are based on immune and gene therapy, or in the use of agents with latency reversing properties. Moreover, acute HIV infection and the impact of early antiretroviral treatment (ART) initiation is another key issue of current research. It has been demonstrated that ART initiation during acute HIV infection minimizes the establishment of the latent HIV reservoir...
May 23, 2017: AIDS Reviews
https://www.readbyqxmd.com/read/28527722/crispr-cas9-mediated-ccr5-ablation-in-human-hematopoietic-stem-progenitor-cells-confers-hiv-1-resistance-in%C3%A2-vivo
#3
Lei Xu, Huan Yang, Yang Gao, Zeyu Chen, Liangfu Xie, Yulin Liu, Ying Liu, Xiaobao Wang, Hanwei Li, Weifeng Lai, Yuan He, Anzhi Yao, Liying Ma, Yiming Shao, Bin Zhang, Chengyan Wang, Hu Chen, Hongkui Deng
Transplantation of hematopoietic stem cells (HSCs) with a naturally occurring CCR5 mutation confers a loss of detectable HIV-1 in the patient, making ablation of the CCR5 gene in HSCs an ideal therapy for an HIV-1 cure. Although CCR5 disruption has been attempted in CD4(+) T cells and hematopoietic stem/progenitor cells (HSPCs), efficient gene editing with high specificity and long-term therapeutic potential remains a major challenge for clinical translation. Here, we established a CRISPR/Cas9 gene editing system in human CD34(+) HSPCs and achieved efficient CCR5 ablation evaluated in long-term reconstituted NOD/Prkdc(scid)/IL-2Rγ(null) mice...
May 17, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28520966/clonal-expansion-of-human-immunodeficiency-virus-infected-cells-and-human-immunodeficiency-virus-persistence-during-antiretroviral-therapy
#4
James I Mullins, Lisa M Frenkel
The latent HIV-1 reservoir in blood decays very slowly, even during prolonged suppression of viral replication by antiretroviral therapy (ART). Mechanisms for reservoir persistence include replenishment through low-level viral replication, longevity and homeostatic proliferation of memory T cells, and most recently appreciated, clonal expansion of HIV-infected cells. Clonally expanded cells make up a large and increasing fraction of the residual infected cell population on ART, and insertion of HIV proviruses into certain host cellular genes has been associated with this proliferation...
March 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28500326/intranasal-drug-delivery-of-small-interfering-rna-targeting-beclin1-encapsulated-with-polyethylenimine-pei-in-mouse-brain-to-achieve-hiv-attenuation
#5
Myosotys Rodriguez, Jessica Lapierre, Chet Raj Ojha, Ajeet Kaushik, Elena Batrakova, Fatah Kashanchi, Seth M Dever, Madhavan Nair, Nazira El-Hage
We previously reported that activation of the host autophagic protein, Beclin1, by HIV-1 infection represents an essential mechanism in controlling HIV replication and viral-induced inflammatory responses in microglial cells. Existing antiretroviral therapeutic approaches have been limited in their ability to cross the blood-brain barrier effectively and recognize and selectively eliminate persistent HIV-infected brain reservoirs. In the present study and for the first time, the bio-distribution and efficacy of noninvasive intranasal delivery of small interfering RNA (siRNA) against the Beclin1 gene using the cationic linear polyethylenimines (PEI) as a gene carrier was investigated in adult mouse brain...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28493944/a-decade-of-viral-mutations-and-associated-drug-resistance-in-a-population-of-hiv-1-puerto-ricans-2002-2011
#6
Lycely Del C Sepúlveda-Torres, Lavanya Rishishwar, Maria Luisa Rogers, Eddy Ríos-Olivares, Nawal Boukli, I King Jordan, Luis A Cubano
Puerto Rico has one of the highest rates of HIV/AIDS seen for any US state or territory, and antiretroviral therapy has been a mainstay of efforts to mitigate the HIV/AIDS public health burden on the island. We studied the evolutionary dynamics of HIV-1 mutation and antiretroviral drug resistance in Puerto Rico by monitoring the population frequency of resistance-associated mutations from 2002 to 2011. Whole blood samples from 4,475 patients were analyzed using the TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System in the Immunoretrovirus Research Laboratory at Universidad Central del Caribe...
2017: PloS One
https://www.readbyqxmd.com/read/28493473/dysregulation-of-mitochondrial-bioenergetics-and-quality-control-by-hiv-1-tat-in-cardiomyocytes
#7
Farzaneh G Tahrir, Santhanam Shanmughapriya, Taha Mohseni Ahooyi, Tijana Knezevic, Manish K Gupta, Christopher D Kontos, Joseph M McClung, Muniswamy Madesh, Jennifer Gordon, Arthur M Feldman, Joseph Y Cheung, Kamel Khalili
Cardiovascular disease remains a leading cause of morbidity and mortality in HIV positive patients, even in those whose viral loads are well controlled with antiretroviral therapy. However, the underlying molecular events responsible for the development of cardiac disease in the setting of HIV remain unknown. The HIV encoded Tat protein plays a critical role in the activation of HIV gene expression and profoundly impacts homeostasis in both HIV infected cells and uninfected cells that have taken up released Tat via a bystander effect...
May 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28490595/sensing-of-hiv-1-entry-triggers-a-type-i-interferon-response-in-human-primary-macrophages
#8
Jérémie Decalf, Marion Desdouits, Vasco Rodrigues, François-Xavier Gobert, Matteo Gentili, Santy Marques-Ladeira, Célia Chamontin, Marylène Mougel, Bruna Cunha de Alencar, Philippe Benaroch
Along with CD4+ T lymphocytes, macrophages are a major cellular source of HIV-1 replication, and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse-transcription, remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection...
May 10, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28490364/sporadic-late-onset-nemaline-myopathy-clinico-pathological-characteristics-and-review-of-76-cases
#9
REVIEW
Lukas J Schnitzler, Tobias Schreckenbach, Aleksandra Nadaj-Pakleza, Werner Stenzel, Elisabeth J Rushing, Philip Van Damme, Andreas Ferbert, Susanne Petri, Christian Hartmann, Antje Bornemann, Andreas Meisel, Jens A Petersen, Thomas Tousseyn, Dietmar R Thal, Jens Reimann, Peter De Jonghe, Jean-Jacques Martin, Peter Y Van den Bergh, Jörg B Schulz, Joachim Weis, Kristl G Claeys
BACKGROUND: Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking. METHODS: We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966-2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases...
May 11, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28485382/single-cell-profiling-of-lineage-determining-transcription-factors-in-antigen-specific-cd4-t-cells-reveals-unexpected-complexity-in-recall-responses-during-immune-reconstitution
#10
Chansavath Phetsouphanh, Yin Xu, Mee Ling Munier, John J Zaunders, Anthony D Kelleher
Recent studies of protein and gene expression at the single-cell level have revealed that the memory T-cell compartment is more heterogeneous than previously acknowledged. Identifying different T helper subsets involved in memory responses at the single-cell level is thus necessary to understand the level of heterogeneity within this population. Antigen-specific CD4(+) T cells were measured using the CD25/OX40 assay together with a qualitative multiplex single-cell RT-PCR assay. Transcription profiles and subset proportions within the antigen-specific CD4(+) T-cell population were dissected...
May 9, 2017: Immunology and Cell Biology
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
#11
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/28471431/current-application-of-crispr-cas9-gene-editing-technique-to-eradication-of-hiv-aids
#12
REVIEW
Z Huang, A Tomitaka, A Raymond, M Nair
Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) remains a major health hazard despite significant advances in prevention and treatment of HIV infection. The major reason for the persistence of HIV/AIDS is the inability of existing treatments to clear or eradicate the multiple HIV reservoirs that exist in the human body. To suppress the virus replication and rebound, HIV/AIDS patients must take life-long antiviral medications. The clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) system is an emerging gene-editing technique with the potential to eliminate or disrupt HIV-integrated genomes or HIV-infected cells from multiple HIV reservoirs, which could result in the complete cure of HIV/AIDS...
May 4, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28471170/resveratrol-reactivates-latent-hiv-through-increasing-histone-acetylation-and-activating-heat-shock-factor-1
#13
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)...
May 23, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28462923/similarity-in-viral-and-host-promoters-couples-viral-reactivation-with-host-cell-migration
#14
Kathrin Bohn-Wippert, Erin N Tevonian, Melina R Megaridis, Roy D Dar
Viral-host interactomes map the complex architecture of an evolved arms race during host cell invasion. mRNA and protein interactomes reveal elaborate targeting schemes, yet evidence is lacking for genetic coupling that results in the co-regulation of promoters. Here we compare viral and human promoter sequences and expression to test whether genetic coupling exists and investigate its phenotypic consequences. We show that viral-host co-evolution is imprinted within promoter gene sequences before transcript or protein interactions...
May 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/28460414/crispr-editing-technology-in-biological-and-biomedical-investigation
#15
Martyn K White, Rafal Kaminski, Won-Bin Young, Pamela C Roehm, Kamel Khalili
The CRISPR or clustered regularly interspaced short palindromic repeats system is currently the most advanced approach to genome editing and is notable for providing an unprecedented degree of specificity, effectiveness and versatility in genetic manipulation. CRISPR evolved as a prokaryotic immune system to confer provide an acquired immunity and resistance to foreign genetic elements such as bacteriophages. It has recently been developed into a tool for the specific targeting of nucleotide sequences within complex eukaryotic genomes for the purpose of genetic manipulation...
April 29, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28450931/cell-penetrating-peptide-of-sodium-iodide-symporter-effect-on-the-i-131-radiotherapy-on-thyroid-cancer
#16
Yi-Xiang Fan, Zhi-Xin Liang, Qing-Zhu Liu, Han Xiao, Ke-Bin Li, Ji-Zhen Wu
The aim of the present study was to clarify whether the cell penetrating peptide of sodium-iodide symporter (NIS) has an effect on the I-131 radiotherapy of thyroid cancer. Firstly, we combined the HIV-1 TAT peptide (a cell penetrating peptide, dTAT) and established a nanoparticle vector (dTAT NP) to study the delivery efficiency of this cell-penetrating strategy for tumor-targeted gene delivery. dTAT NP was transfected into cultured TPC-1 cells as a model to study the effects of I-131 radiotherapy on thyroid cancer...
March 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28447399/genome-wide-association-study-of-hiv-associated-neurocognitive-disorder-hand-a-charter-group-study
#17
Peilin Jia, Zhongming Zhao, Todd Hulgan, William S Bush, David C Samuels, Cinnamon S Bloss, Robert K Heaton, Ronald J Ellis, Nicholas Schork, Christina M Marra, Ann C Collier, David B Clifford, Benjamin B Gelman, Ned Sacktor, Susan Morgello, David M Simpson, J Allen McCutchan, Jill S Barnholtz-Sloan, Donald R Franklin, Debralee Rosario, Scott L Letendre, Igor Grant, Asha R Kallianpur
HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded...
June 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/28443132/disease-resistance-and-the-definition-of-genetic-enhancement
#18
Derek So, Erika Kleiderman, Seydina B Touré, Yann Joly
Recent gene editing experiments carried out in human embryos have raised the question of whether interventions like the introduction of a CCR5-Δ32 deletion, which could provide heritable resistance to HIV infection, ought to be considered enhancements. Many authors have used the term "enhancement" in different ways, some based on patients' biomedical outcomes and others on their social context. These classifications are often considered overly imprecise. Nevertheless, the concept of "enhancement" could affect the ways in which these applications are regulated in different jurisdictions, the availability of coverage by insurers or public health care, and the force of public opinion in shaping future policy on gene editing...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28442603/aspergillus-fumigatus-trehalose-regulatory-subunit-homolog-moonlights-to-mediate-cell-wall-homeostasis-through-modulation-of-chitin-synthase-activity
#19
Arsa Thammahong, Alayna K Caffrey-Card, Sourabh Dhingra, Joshua J Obar, Robert A Cramer
Trehalose biosynthesis is found in fungi but not humans. Proteins involved in trehalose biosynthesis are essential for fungal pathogen virulence in humans and plants through multiple mechanisms. Loss of canonical trehalose biosynthesis genes in the human pathogen Aspergillus fumigatus significantly alters cell wall structure and integrity, though the mechanistic link between these virulence-associated pathways remains enigmatic. Here we characterize genes, called tslA and tslB, which encode proteins that contain domains similar to those corresponding to trehalose-6-phosphate phosphatase but lack critical catalytic residues for phosphatase activity...
April 25, 2017: MBio
https://www.readbyqxmd.com/read/28422792/progress-in-hiv-1-antibody-research-using-humanized-mice
#20
Henning Gruell, Florian Klein
PURPOSE OF REVIEW: Recent discoveries of highly potent broadly HIV-1 neutralizing antibodies provide new opportunities to successfully prevent, treat, and potentially cure HIV-1 infection. To test their activity in vivo, humanized mice have been shown to be a powerful model and were used to investigate antibody-mediated prevention and therapy approaches. In this review, we will summarize recent findings in humanized mice that have informed on the potential use of broadly neutralizing antibodies targeting HIV-1 in humans...
May 2017: Current Opinion in HIV and AIDS
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