An Alternative and Effective HIV Vaccination Approach Based on Inhibition of Antigen Presentation Attenuators in Dendritic Cells

Song, Xiao Tong; Evel-Kabler, Kevin; Rollins, Lisa; Aldrich, Melissa B.; Gao, Feng; Huang, Xue F.; Chen, Si Yi

doi:10.1371/journal.pmed.0030011

Cited by 79 publications

(76 citation statements)

References 74 publications

(110 reference statements)

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“…(E) Mucosal HIV gp120-specific sIgA titers from the pooled sample of each group (4-6 mice/group) were quantified by capture ELISA. Antibody titers are reported as the mean ± SD of endpoint titers (36). Data from 1 experiment representative of 3 are presented.…”

Section: Figurementioning

confidence: 99%

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

Hong

Song²,

Rollins³

et al. 2011

J. Clin. Invest.

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Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20 -an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs -restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses.

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Section: Figurementioning

confidence: 99%

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

Hong

Song²,

Rollins³

et al. 2011

J. Clin. Invest.

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“…[4][5][6][7][8] An effective siRNA has to be stable in order to achieve long-term inhibition of target genes. In fact, the half-life of unmodified siRNAs is short, especially in vivo, due to rapid elimination by the kidney and rapid degradation by serum RNases, with a half-life of o10 min.…”

Section: Introductionmentioning

confidence: 99%

Intratumor RNA interference of cell cycle genes slows down tumor progression

et al. 2011

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Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clinical application of such molecules as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing molecules involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technology from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were observed. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.

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“…Song and colleagues did not observe any obvious signs of pathology 7 months after the mice were immunised with the SOCS1-suppressed DCs [26], but the same may not be the case in humans. SOCS1 is required for curtailing interferon-mediated inflammation [4], reducing DC-mediated autoimmunity [13] and also appears to play an anti-cancer role [5].…”

Section: Future Perspectivementioning

confidence: 98%

“…Indeed this was proposed in 2006 (albeit from a different perspective) when Song and coworkers used RNAi against SOCS1 to enhance anti-HIV responses in mice [26]. In that study murine dendritic cells (DCs)…”

Section: Future Perspectivementioning

confidence: 99%

Socs1: A Host Factor Required for HIV-1 Gag Trafficking

Sivakumaran

Harrich²

2008

Future HIV Ther.

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Evaluation of: Ryo A, Tsurutani N, Ohba K et al.: SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag. Proc. Natl Acad. Sci. USA 105, 294–299 (2008). Gag is an essential HIV protein that is responsible for assembling infectious viral particles. The journey of Gag from synthesis to virion formation is an attractive target for anti-HIV therapy. While a lot is known about the cellular factors required for virion assembly and budding, relatively little is known about factors required for Gag trafficking. Ryo and colleagues provide the first evidence of such a factor, the suppressor of cytokine signaling (SOCS)1. They demonstrated that SOCS1 is important for Gag stability and plays a critical role in its trafficking within the cell. Without SOCS1 Gag accumulates in perinuclear bodies and is degraded by lysosomes. This article therefore highlights a new and novel target for stopping the production of HIV, a target that belongs to the relatively invariant host rather than the rapidly evolving virus.

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An Alternative and Effective HIV Vaccination Approach Based on Inhibition of Antigen Presentation Attenuators in Dendritic Cells

Cited by 79 publications

References 74 publications

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

Intratumor RNA interference of cell cycle genes slows down tumor progression

Socs1: A Host Factor Required for HIV-1 Gag Trafficking

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