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Non-VLPs
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
The CRISPR/guide RNA technique, which involved screening of 16 MS2-mediated single-guide RNAs, led to a highly effective and target-specific Cas9 system that could serve as a novel HIV-latency-reversing therapeutic tool for the permanent elimination of HIV-1 latent reservoirs (Zhang Y et al. 2015). Furthermore, the MS2 coat fusions together with the MS2 stem-loops were applied by specific induction of endogenous viral restriction factors using CRISPR/Cas-derived transcriptional activators (Bogerd et al. 2015). The RNA-guided dCas9-VP64 reactivated HIV-1 in all latency models tested and did not lead to nonspecific global gene expression or adverse cellular toxicities, therefore providing an exciting new avenue for targeted reactivation of latent HIV (Bialek et al. 2016; Limsirichai et al. 2016; Saayman et al. 2016; Zhang Y et al. 2018). The successful application of the CRISPR-Cas9 approach against HIV-1 was reviewed in detail (Darcis et al. 2018; Wang Gang et al. 2018). Furthermore, the CRISPR-mediated activation of endogenous BST-2/tetherin expression was shown to inhibit the wild-type HIV-1 production (Zhang Y et al. 2019).
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
Lack of viral dissemination within the host remains a key measure of safety: as noted, innate and adaptive immune mechanisms are active in normal cells and tissues but defective or suppressed in tumors, which is key to the tumor-selectivity of this virus (as well as most oncolytic viruses) and its lack of systemic dissemination. Indeed, in preclinical studies, vector biodistribution occurred over time in lymphoid tissues of athymic nude mice lacking T cell-mediated adaptive immunity, and in permissive BALB/c mice which are the natural hosts for MLV due to their genetic defects in innate anti-retroviral immunity. However, RRV infection and spread was found to be restricted in fully immune-competent mouse strains [35,58] and in rats [44]. While amphotropic MLV can enter human lymphocytes and integrate into the host genome, vector spread has been shown to be inefficient in primary lymphocytes in culture [2,89]. Any infected lymphocytes prevent further virus replication through innate antiretroviral defense mechanisms (e.g. APOBEC3-F and -G, tetherin), and are eventually cleared through adaptive immune responses recognizing viral peptides presented by MHC on the cell surface. Accordingly, it seems unlikely that Toca 511 dissemination could happen by means of viral spread from infected lymphoid cells.
Understanding extracellular vesicle diversity – current status
Published in Expert Review of Proteomics, 2018
David W. Greening, Richard J. Simpson
Members of the Rab GTPase family (including Rab 5/7/11/27/35) have been shown to modulate exosome trafficking and thought to act on different MVBs along these different endocytic pathways [131–134]. Further, V-ATPase was shown to be a key regulator of both cholesterol trafficking and endosome fate, with a significant increase in PM-associated exosomes when V-ATPase is inhibited [135]. The microtubule and cytoskeletal network has been recognized to regulate intracellular organization and transport MVEs, in coordination with molecular motors, to the site of release (reviewed [136]). For example, RAB27A and RAB27B (together with effectors, SYTL4 and EXPH5) act in the docking of MVEs to the PM in order to promote their fusion [134] and this mechanism requires the rearrangement of the actin cytoskeleton [137]. Further, RAB27A/B has been shown to facilitate the docking of MVBs to the PM, with reduction in exosome secretion after RAB27A silencing; this strategy is now commonly used as a way of modulating exosome secretion [138,139]. Further, it is well known that specific lipid components, e.g. cholesterol, sphingomyelin, phosphoinositides endow regions of the PM with preferential capability to bind SNAREs and MVEs [140]. This suggests that the composition of the limiting membranes of MVEs may modulate their target location by acting on the motility of MVEs. However, not much is known regarding the fusogenic machinery implicated in exosome release. Recently, the PM-associated protein tetherin has been shown as a exosomal tether, causing PM pooling of exosomes as imaged by fluorescence microscopy and correlative light/cryo-immuno/scanning electron microscopy [141]. Phosphorylated SNAP23 has been shown to enable exosome release [142,143], in addition to MAP kinase PMK-1 [144], the morphogen Bmp [3], and Rab35 involved in a parallel recycling pathway to Rab11 and assists to traffic endosomes to the PM [145]. It is not known whether each of these pathways and tethering components acts on different MVBs or, concomitantly, on the same MVB. Future studies employing super-resolution microscopy and targeted molecular biology are needed to address spatial and temporal regulation of MVBs to the PM for exosome secretion. For example, optical tweezers have been shown to allow manipulation and visualization of individual exosomes from a subset lacking CD63 expression at the surface of recipient cells [146]. Alternative mechanisms of exosome release involve membrane fusion using a specific combination of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) including vesicular SNAREs (v-SNAREs) localized on MVBs; these interact with target SNAREs (t-SNAREs) on the intracellular PM [147–149], release of cytoplasmic Ca2+ [150], inflammatory response (IFN-γ) [151], and cytoplasmic tyrosine kinase SRC [152] (reviewed [30]).