RevM10-expressing T cells derived in vivo from transduced human hematopoietic stem-progenitor cells inhibit human immunodeficiency virus replication

Bonyhadi, Mark; Moss, Katherine G.; Voytovich, Amy; Auten, Jennifer; Kalfoglou, Creton; Plavec, Ivan; Forestell, Sean; Su, Lishan; Böhnlein, Ernst; Kaneshima, Hideto

doi:10.1128/jvi.71.6.4707-4716.1997

Cited by 96 publications

(17 citation statements)

References 43 publications

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“…This conjoint organ provides a microenvironment for long‐term T‐lineage differentiation. Importantly, we and others have previously shown that direct injection of exogenous CD34+ human hematopoietic progenitor cells into Thy/Liv implants in sublethally irradiated SCID‐hu mice results in engraftment and T‐lymphoid differentiation of the exogenous cells [9, 19–21].…”

Section: Resultsmentioning

confidence: 99%

Generation of T Lineage Cells from Human Embryonic Stem Cells in a Feeder Free System

et al. 2009

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Human embryonic stem cells (hESC) have the potential to revolutionize certain medical treatments, including T-cellbased therapies. However, optimal approaches to develop T cells from hESC are lacking. In this report, we show that T-cell progenitors can be derived from hESC cultured as embryoid bodies (EBs). These EB-derived T-cell progenitors give rise to phenotypically and functionally normal cells of the T lineage when transferred into human thymic tissue implanted in immunocompromised mice, suggesting that introduction of these progenitors into patients may also yield functional T cells. Moreover, hematopoietic progenitors demonstrating T-cell potential appeared to be CD45؉/CD34؉, resembling those found in normal bone marrow. In contrast to T cells developed from hESC cocultured on murine stromal cells, the EB-derived T cells also expressed normal levels of CD45. Importantly, the EB system eliminates the previous need for murine cocultures, a key impediment to developing a protocol for T-cell progenitor derivation suitable for clinical use. Furthermore, following lentiviral-mediated introduction of a vector expressing enhanced green fluorescent protein into hESC, stable transgene expression was maintained throughout differentiation, suggesting a potential for gene therapy approaches aimed at the augmentation of T-cell function or treatment of T-cell disorders.

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Section: Resultsmentioning

confidence: 99%

Generation of T Lineage Cells from Human Embryonic Stem Cells in a Feeder Free System

et al. 2009

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“…When expressed in transfected cells, this mutant Rev protein successfully inhibited the function of its wild-type counterpart. That RevM10 serves as an effective trans-dominant inhibitor of Rev function was further validated by others [40][41][42][43][44] thereby catapulting RevM10-based gene therapy into Phase I and II clinical trials [45]. However, a subsequent study by Hamm et al [46], involving passage of HIV-1 in a T-cell line constitutively expressing RevM10, reported rapid emergence of a RevM10-resistant virus [46].…”

Section: Resistance To Trans-dominant Revm10 Therapy Induces a Conformentioning

confidence: 99%

Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element

Sherpa¹,

Grice²

2020

Viruses

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Nucleocytoplasmic transport of unspliced and partially spliced human immunodeficiency virus (HIV) RNA is mediated in part by the Rev response element (RRE), a ~350 nt cis-acting element located in the envelope coding region of the viral genome. Understanding the interaction of the RRE with the viral Rev protein, cellular co-factors, and its therapeutic potential has been the subject of almost three decades of structural studies, throughout which a recurring discussion theme has been RRE topology, i.e., whether it comprises 4 or 5 stem-loops (SLs) and whether this has biological significance. Moreover, while in vitro mutagenesis allows the construction of 4 SL and 5 SL RRE conformers and testing of their roles in cell culture, it has not been immediately clear if such findings can be translated to a clinical setting. Herein, we review several articles demonstrating remarkable flexibility of the HIV-1 and HIV-2 RREs following initial observations that HIV-1 resistance to trans-dominant Rev therapy was founded in structural rearrangement of its RRE. These observations can be extended not only to cell culture studies demonstrating a growth advantage for the 5 SL RRE conformer but also to evolution in RRE topology in patient isolates. Finally, RRE conformational flexibility provides a target for therapeutic intervention, and we describe high throughput screening approaches to exploit this property.

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“…The antiviral effect of VprIE was also compared to that obtained with RevM10, a trans-dominant mutant form of HIV-1 Rev that has been shown to delay HIV-1 replication in transduced cell lines, primary T cells, and CD34-enriched hematopoietic progenitor stem cells (2,4,27). Jurkat cells were transduced with pBabepuro-RevM10, and the resulting puromycin-resistant population, Jurkat-RevM10 cells, was infected with 100,000 cpm of HxBRU or HxBRU-R-.…”

Section: Protein Expression and Replication Potential Of Hiv-1 Virionmentioning

confidence: 99%

Virion-Targeted Viral Inactivation of Human Immunodeficiency Virus Type 1 by Using Vpr Fusion Proteins

Kobinger

Borsetti

Nie

et al. 1998

J Virol

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Inactivation of progeny virions with chimeric virion-associated proteins represents a novel therapeutic approach against human immunodeficiency virus (HIV) replication. The HIV type 1 (HIV-1) Vpr gene product, which is packaged into virions, is an attractive candidate for such a strategy. In this study, we developed Vpr-based fusion proteins that could be specifically targeted into mature HIV-1 virions to affect their structural organization and/or functional integrity. Two Vpr fusion proteins were constructed by fusing to the first 88 amino acids of HIV-1 Vpr the chloramphenicol acetyltransferase enzyme (VprCAT) or the last 18 C-terminal amino acids of the HIV-1 Vpu protein (VprIE). These Vpr fusion proteins were initially designed to quantify their efficiency of incorporation into HIV-1 virions when produced in cis from the provirus. Subsequently, CD4+ Jurkat T-cell lines constitutively expressing the VprCAT or the VprIE fusion protein were generated with retroviral vectors. Expression of the VprCAT or the VprIE fusion protein in CD4+ Jurkat T cells did not interfere with cellular viability or growth but conferred substantial resistance to HIV replication. The resistance to HIV replication was more pronounced in Jurkat-VprIE cells than in Jurkat-VprCAT cells. Moreover, the antiviral effect mediated by VprIE was dependent on an intact p6 gag domain, indicating that the impairment of HIV-1 replication required the specific incorporation of Vpr fusion protein into virions. Gene expression, assembly, or release was not affected upon expression of these Vpr fusion proteins. Indeed, the VprIE and VprCAT fusion proteins were shown to affect the infectivity of progeny virus, since HIV virions containing the VprCAT or the VprIE fusion proteins were, respectively, 2 to 3 times and 10 to 30 times less infectious than the wild-type virus. Overall, this study demonstrated the successful transfer of resistance to HIV replication in tissue cultures by use of Vpr-based antiviral genes.

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RevM10-expressing T cells derived in vivo from transduced human hematopoietic stem-progenitor cells inhibit human immunodeficiency virus replication

Cited by 96 publications

References 43 publications

Generation of T Lineage Cells from Human Embryonic Stem Cells in a Feeder Free System

Generation of T Lineage Cells from Human Embryonic Stem Cells in a Feeder Free System

Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element

Virion-Targeted Viral Inactivation of Human Immunodeficiency Virus Type 1 by Using Vpr Fusion Proteins

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