keyword
https://read.qxmd.com/read/38512975/virus-specificity-and-nucleoporin-requirements-for-mx2-activity-are-affected-by-gtpase-function-and-capsid-cypa-interactions
#1
JOURNAL ARTICLE
Bailey Layish, Ram Goli, Haley Flick, Szu-Wei Huang, Robert Z Zhang, Mamuka Kvaratskhelia, Melissa Kane
Human myxovirus resistance 2 (MX2/MXB) is an interferon-induced GTPase that inhibits human immunodeficiency virus-1 (HIV-1) infection by preventing nuclear import of the viral preintegration complex. The HIV-1 capsid (CA) is the major viral determinant for sensitivity to MX2, and complex interactions between MX2, CA, nucleoporins (Nups), cyclophilin A (CypA), and other cellular proteins influence the outcome of viral infection. To explore the interactions between MX2, the viral CA, and CypA, we utilized a CRISPR-Cas9/AAV approach to generate CypA knock-out cell lines as well as cells that express CypA from its endogenous locus, but with specific point mutations that would abrogate CA binding but should not affect enzymatic activity or cellular function...
March 21, 2024: PLoS Pathogens
https://read.qxmd.com/read/38496600/combining-cell-intrinsic-and-extrinsic-resistance-to-hiv-1-by-engineering-hematopoietic-stem-cells-for-ccr5-knockout-and-b-cell-secretion-of-therapeutic-antibodies
#2
William N Feist, Sofia E Luna, Kaya Ben-Efraim, Maria V Filsinger Interrante, Nelson A Amorin, Nicole M Johnston, Theodora U J Bruun, Hana Y Ghanim, Benjamin J Lesch, Amanda M Dudek, Matthew H Porteus
Autologous transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5 -null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny...
March 9, 2024: bioRxiv
https://read.qxmd.com/read/38479630/hematopoietic-stem-cell-gene-editing-rescues-b-cell-development-in-x-linked-agammaglobulinemia
#3
JOURNAL ARTICLE
Sameer Bahal, Marta Zinicola, Shefta E Moula, Thomas E Whittaker, Andrea Schejtman, Asma Naseem, Elena Blanco, Winston Vetharoy, Yi-Ting Hu, Rajeev Rai, Eduardo Gomez-Castaneda, Catarina Cunha Santos, Siobhan O Burns, Emma C Morris, Claire Booth, Giandomenico Turchiano, Alessia Cavazza, Adrian J Thrasher, Giorgia Santilli
BACKGROUND: X-linked agammaglobulinemia (XLA) is an inborn error of immunity that renders boys susceptible to life-threatening infections due to loss of mature B cells and circulating immunoglobulins. It is caused by defects in the gene encoding the Bruton's Tyrosine Kinase (BTK) that mediates the maturation of B cells in the bone marrow and their activation in the periphery. Here we report on a gene editing protocol to achieve "knock-in" of a therapeutic BTK cassette in hematopoietic stem and progenitor cells (HSPCs) as a treatment for XLA...
March 11, 2024: Journal of Allergy and Clinical Immunology
https://read.qxmd.com/read/38472686/the-rre-rev-module-has-no-effect-on-the-packaging-efficiency-of-cas9-and-gag-proteins-into-nanomedic-virus-like-particles
#4
JOURNAL ARTICLE
N A Kruglova, D S Komkov, D V Mazurov, M V Shepelev
Delivery of ribonucleoprotein complexes of Cas9 nuclease and guide RNA into target cells with virus-like particles (VLP) is one of the novel methods of genome editing and is suitable for gene therapy of human diseases in the future. The efficiency of genome editing with VLPs depends on the Cas9 packaging into VLPs, the process mediated by the viral Gag protein. To improve the packaging of Cas9 into NanoMEDIC VLPs, plasmid constructs for Cas9 and Gag expression were modified by adding the HIV Rev response element (RRE), which was expected to increase the nuclear export of RRE-containing transcripts into the cytosol via the Rev accessory protein, as described for a Vpr-Cas9-based VLP system...
March 12, 2024: Doklady Biological Sciences: Proceedings of the Academy of Sciences of the USSR, Biological Sciences Sections
https://read.qxmd.com/read/38468291/the-construction-of-modular-universal-chimeric-antigen-receptor-t-mu-car-t-cells-by-covalent-linkage-of-allogeneic-t-cells-and-various-antibody-fragments
#5
JOURNAL ARTICLE
Tao Chen, Jieyi Deng, Yongli Zhang, Bingfeng Liu, Ruxin Liu, Yiqiang Zhu, Mo Zhou, Yingtong Lin, Baijin Xia, Keming Lin, Xiancai Ma, Hui Zhang
BACKGROUND: Chimeric antigen receptor-T (CAR-T) cells therapy is one of the novel immunotherapeutic approaches with significant clinical success. However, their applications are limited because of long preparation time, high cost, and interpersonal variations. Although the manufacture of universal CAR-T (U-CAR-T) cells have significantly improved, they are still not a stable and unified cell bank. METHODS: Here, we tried to further improve the convenience and flexibility of U-CAR-T cells by constructing novel modular universal CAR-T (MU-CAR-T) cells...
March 11, 2024: Molecular Cancer
https://read.qxmd.com/read/38448924/correction-stable-expression-of-hiv-1-mper-extended-epitope-on-the-surface-of-the-recombinant-probiotic-bacteria-escherichia-coli-nissle-1917-using-crispr-cas9
#6
Nathaniel Ninyio, Katharina Schmitt, Gladys Sergon, Charlotta Nilsson, Sören Andersson, Nikolai Scherbak
No abstract text is available yet for this article.
March 6, 2024: Microbial Cell Factories
https://read.qxmd.com/read/38411080/crispr-cas9-screen-of-e3-ubiquitin-ligases-identifies-traf2-and-uhrf1-as-regulators-of-hiv-latency-in-primary-human-t-cells
#7
JOURNAL ARTICLE
Ujjwal Rathore, Paige Haas, Vigneshwari Easwar Kumar, Joseph Hiatt, Kelsey M Haas, Mehdi Bouhaddou, Danielle L Swaney, Erica Stevenson, Lorena Zuliani-Alvarez, Michael J McGregor, Autumn Turner-Groth, Charles Ochieng' Olwal, Yaw Bediako, Hannes Braberg, Margaret Soucheray, Melanie Ott, Manon Eckhardt, Judd F Hultquist, Alexander Marson, Robyn M Kaake, Nevan J Krogan
During HIV infection of CD4+ T cells, ubiquitin pathways are essential to viral replication and host innate immune response; however, the role of specific E3 ubiquitin ligases is not well understood. Proteomics analyses identified 116 single-subunit E3 ubiquitin ligases expressed in activated primary human CD4+ T cells. Using a CRISPR-based arrayed spreading infectivity assay, we systematically knocked out 116 E3s from activated primary CD4+ T cells and infected them with NL4-3 GFP reporter HIV-1. We found 10 E3s significantly positively or negatively affected HIV infection in activated primary CD4+ T cells, including UHRF1 (pro-viral) and TRAF2 (anti-viral)...
February 27, 2024: MBio
https://read.qxmd.com/read/38400066/pten-mediates-the-silencing-of-unintegrated-hiv-1-dna
#8
JOURNAL ARTICLE
An Thanh Phan, Yiping Zhu
The integration of viral DNA into a host genome is an important step in HIV-1 replication. However, due to the high failure rate of integration, the majority of viral DNA exists in an unintegrated state during HIV-1 infection. In contrast to the robust expression from integrated viral DNA, unintegrated HIV-1 DNA is very poorly transcribed in infected cells, but the molecular machinery responsible for the silencing of unintegrated HIV-1 DNA remains poorly characterized. In this study, we sought to characterize new host factors for the inhibition of expression from unintegrated HIV-1 DNA...
February 14, 2024: Viruses
https://read.qxmd.com/read/38400062/hiv-1-proviral-genome-engineering-with-crispr-cas9-for-mechanistic-studies
#9
JOURNAL ARTICLE
Usman Hyder, Ashutosh Shukla, Ashwini Challa, Iván D'Orso
HIV-1 latency remains a barrier to a functional cure because of the ability of virtually silent yet inducible proviruses within reservoir cells to transcriptionally reactivate upon cell stimulation. HIV-1 reactivation occurs through the sequential action of host transcription factors (TFs) during the "host phase" and the viral TF Tat during the "viral phase", which together facilitate the positive feedback loop required for exponential transcription, replication, and pathogenesis. The sequential action of these TFs poses a challenge to precisely delineate the contributions of the host and viral phases of the transcriptional program to guide future mechanistic and therapeutic studies...
February 13, 2024: Viruses
https://read.qxmd.com/read/38390557/gesicles-packaging-dcas9-vpr-ribonucleoprotein-complexes-can-combine-with-vorinostat-and-promote-hiv-proviral-transcription
#10
JOURNAL ARTICLE
Michaela A Fisher, Waj Chaudhry, Lee A Campbell
Despite the success of combination antiretroviral therapy (cART) in HIV treatment, a cure for HIV remains elusive. Scientists postulate that HIV latent reservoirs may be a vital target in curative strategies. Vorinostat is a latency-reversing agent that has demonstrated some effectiveness in reactivating latent HIV, but complementary therapies may be essential to enhance its efficacy. One such approach may utilize the CRISPR-Cas9 system, which has evolved to include transcriptional activators such as dCas9-VPR...
March 14, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38355914/hiv-1-mrna-knockdown-with-crispr-cas9-enhances-neurocognitive-function
#11
JOURNAL ARTICLE
Kristen A McLaurin, Hailong Li, Kamel Khalili, Charles F Mactutus, Rosemarie M Booze
Mixed glia are infiltrated with HIV-1 virus early in the course of infection leading to the development of a persistent viral reservoir in the central nervous system. Modification of the HIV-1 genome using gene editing techniques, including CRISPR/Cas9, has shown great promise towards eliminating HIV-1 viral reservoirs; whether these techniques are capable of removing HIV-1 viral proteins from mixed glia, however, has not been systematically evaluated. Herein, the efficacy of adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing for eliminating HIV-1 messenger RNA (mRNA) from cortical mixed glia was evaluated in vitro and in vivo...
February 14, 2024: Journal of Neurovirology
https://read.qxmd.com/read/38328062/high-resolution-inference-of-multiplexed-anti-hiv-gene-editing-using-single-cell-targeted-dna-sequencing
#12
Mohamed S Bouzidi, Zain Y Dossani, Carolina Di Benedetto, Kyle A Raymond, Shivani Desai, Leonard R Chavez, Paola Betancur, Satish K Pillai
UNLABELLED: Gene therapy-based HIV cure strategies typically aim to excise the HIV provirus directly, or target host dependency factors (HDFs) that support viral persistence. Cure approaches will likely require simultaneous co-targeting of multiple sites within the HIV genome to prevent evolution of resistance, and/or co-targeting of multiple HDFs to fully render host cells refractory to HIV infection. Bulk cell-based methods do not enable inference of co-editing within individual viral or target cell genomes, and do not discriminate between monoallelic and biallelic gene disruption...
January 24, 2024: bioRxiv
https://read.qxmd.com/read/38311724/stable-expression-of-hiv-1-mper-extended-epitope-on-the-surface-of-the-recombinant-probiotic-bacteria-escherichia-coli-nissle-1917-using-crispr-cas9
#13
JOURNAL ARTICLE
Nathaniel Ninyio, Katherina Schmitt, Gladys Sergon, Charlotta Nilsson, Sören Andersson, Nikolai Scherbak
BACKGROUND: Mucosal vaccines have the potential to induce protective immune responses at the sites of infection. Applying CRISPR/Cas9 editing, we aimed to develop a probiotic-based vaccine candidate expressing the HIV-1 envelope membrane-proximal external region (MPER) on the surface of E. coli Nissle 1917. RESULTS: The HIV-1 MPER epitope was successfully introduced in the porin OmpF of the E. coli Nissle 1917 (EcN-MPER) and the modification was stable over 30 passages of the recombinant bacteria on the DNA and protein level...
February 4, 2024: Microbial Cell Factories
https://read.qxmd.com/read/38255224/increasing-gene-editing-efficiency-via-crispr-cas9-or-cas12a-mediated-knock-in-in-primary-human-t-cells
#14
REVIEW
Natalia Kruglova, Mikhail Shepelev
T lymphocytes represent a promising target for genome editing. They are primarily modified to recognize and kill tumor cells or to withstand HIV infection. In most studies, T cell genome editing is performed using the CRISPR/Cas technology. Although this technology is easily programmable and widely accessible, its efficiency of T cell genome editing was initially low. Several crucial improvements were made in the components of the CRISPR/Cas technology and their delivery methods, as well as in the culturing conditions of T cells, before a reasonable editing level suitable for clinical applications was achieved...
January 6, 2024: Biomedicines
https://read.qxmd.com/read/38211593/activation-neutral-gene-editing-of-tonsillar-cd4-t%C3%A2-cells-for-functional-studies-in-human-ex%C3%A2-vivo-tonsil-cultures
#15
JOURNAL ARTICLE
Katharina Morath, Lopamudra Sadhu, Gerhard Dyckhoff, Madeleine Gapp, Oliver T Keppler, Oliver T Fackler
The molecular and immunological properties of tissue-resident resting CD4 T cells are understudied due to the lack of suitable gene editing methods. Here, we describe the ex vivo culture and gene editing methodology ediTONSIL for CD4 T cells from human tonsils. Optimized CRISPR-Cas9 RNP nucleofection results in knockout efficacies of over 90% without requiring exogenous activation. Editing can be performed on multiple cell types in bulk cultures or on isolated CD4 T cells that can be labeled and reintroduced into their tissue environment...
January 4, 2024: Cell Rep Methods
https://read.qxmd.com/read/38201268/advancements-in-cell-based-therapies-for-hiv-cure
#16
REVIEW
Yusuke Matsui, Yasuo Miura
The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV transmission. However, despite the success of these regimens, the global HIV epidemic persists, prompting a comprehensive exploration of potential strategies for an HIV cure...
December 28, 2023: Cells
https://read.qxmd.com/read/38190037/efficient-editing-of-the-cxcr4-locus-using-cas9-ribonucleoprotein-complexes-stabilized-with-polyglutamic-acid
#17
JOURNAL ARTICLE
D S Golubev, D S Komkov, M V Shepelev, D V Mazurov, N A Kruglova
Gene editing using the CRISPR/Cas9 system provides new opportunities to treat human diseases. Approaches aimed at increasing the efficiency of genome editing are therefore important to develop. To increase the level of editing of the CXCR4 locus, which is a target for gene therapy of HIV infection, the Cas9 protein was modified by introducing additional NLS signals and ribonucleoprotein complexes of Cas9 and guide RNA were stabilized with poly-L-glutamic acid. The approach allowed a 1.8-fold increase in the level of CXCR4 knockout in the CEM/R5 T cell line and a 2-fold increase in the level of knock-in of the HIV-1 fusion peptide inhibitor MT-C34 in primary CD4+ T lymphocytes...
January 8, 2024: Doklady Biological Sciences: Proceedings of the Academy of Sciences of the USSR, Biological Sciences Sections
https://read.qxmd.com/read/38164106/crispr-cas-as-a-powerful-tool-for-human-immunodeficiency-virus-cure-a-review
#18
JOURNAL ARTICLE
Shirley Vasconcelos Komninakis, Wilson Domingues, Sabri Saeed Sanabani, Victor Angelo Folgosi, Igor Neves Barbosa, Jorge Casseb
Despite care and the availability of effective antiretroviral treatment, some human immunodeficiency virus (HIV)-infected individuals suffer from neurocognitive disorders associated with HIV (HAND) that significantly affect their quality of life. The different types of HAND can be divided into asymptomatic neurocognitive impairment, mild neurocognitive disorder, and the most severe form known as HIV-associated dementia. Little is known about the mechanisms of HAND, but it is thought to be related to infection of astrocytes, microglial cells, and macrophages in the human brain...
February 2, 2024: AIDS Research and Human Retroviruses
https://read.qxmd.com/read/38149977/eliminating-the-hiv-tissue-reservoir-current-strategies-and-challenges
#19
REVIEW
Kangpeng Li, Qiang Zhang
BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is still one of the most widespread and harmful infectious diseases in the world. The presence of reservoirs housing the human immunodeficiency virus (HIV) represents a significant impediment to the development of clinically applicable treatments on a large scale. The viral load in the blood can be effectively reduced to undetectable levels through antiretroviral therapy (ART), and a higher concentration of HIV is sequestered in various tissues throughout the body, forming the tissue reservoir - the source of viremia after interruption treatment...
December 27, 2023: Infectious Diseases
https://read.qxmd.com/read/38134881/a-histone-deacetylase-network-regulates-epigenetic-reprogramming-and-viral-silencing-in-hiv-infected-cells
#20
JOURNAL ARTICLE
Jackson J Peterson, Catherine A Lewis, Samuel D Burgos, Ashokkumar Manickam, Yinyan Xu, Allison A Rowley, Genevieve Clutton, Brian Richardson, Fei Zou, Jeremy M Simon, David M Margolis, Nilu Goonetilleke, Edward P Browne
A long-lived latent reservoir of HIV-1-infected CD4 T cells persists with antiretroviral therapy and prevents cure. We report that the emergence of latently infected primary CD4 T cells requires the activity of histone deacetylase enzymes HDAC1/2 and HDAC3. Data from targeted HDAC molecules, an HDAC3-directed PROTAC, and CRISPR-Cas9 knockout experiments converge on a model where either HDAC1/2 or HDAC3 targeting can prevent latency, whereas all three enzymes must be targeted to achieve latency reversal...
December 21, 2023: Cell Chemical Biology
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