Adenoviral Vector Immunity: Its Implications and Circumvention Strategies

Ahi, Yadvinder S.; Bangari, Dinesh S.; Mittal, Suresh K.

doi:10.2174/156652311796150372

Cited by 160 publications

(71 citation statements)

References 220 publications

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“…The immune system poses an important obstacle for the success of gene therapies with viral vectors [1], [2]. Conceivably, the immune system has evolved to fight prevalent microbial intruders which are often used as vehicles for therapeutic transgenes.…”

Section: Introductionmentioning

confidence: 99%

Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus

et al. 2014

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The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell-deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-naïve WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-naïve mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors.

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Section: Introductionmentioning

confidence: 99%

Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus

et al. 2014

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“…Little-to-no evidence of such toxicity actually exists, however, in the great many clinical trials that have used Ad vectors during the past 2 decades, including our own. 34–36 This may be especially true for delivery such as in the current application using local administration, wherein vector cell entry occurs well before systemic immunity can develop. Although we did not observe any myocardial inflammation or other adverse effects in rats that had received Ad, additional studies to clarify immunologic response are underway.…”

Section: Discussionmentioning

confidence: 99%

In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: Implications for clinical myocardial regeneration

Mathison

Singh

Chiuchiolo

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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Objective The reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells improves ventricular function in myocardial infarction models. Only integrating persistent expression vectors have thus far been used to induce reprogramming, potentially limiting its clinical applicability. We therefore tested the reprogramming potential of nonintegrating, acute expression adenoviral (Ad) vectors. Methods Ad or lentivirus vectors encoding Gata4 (G), Mef2c (M), and Tbx5 (T) were validated in vitro. Sprague-Dawley rats then underwent coronary ligation and Ad-mediated administration of vascular endothelial growth factor to generate infarct prevascularization. Three weeks later, animals received Ad or lentivirus encoding G, M, or T (AdGMT or LentiGMT) or an equivalent dose of a null vector (n = 11, 10, and 10, respectively). Outcomes were analyzed by echocardiography, magnetic resonance imaging, and histology. Results Ad and lentivirus vectors provided equivalent G, M, and T expression in vitro. AdGMT and LentiGMT both likewise induced expression of the cardiomyocyte marker cardiac troponin T in approximately 6% of cardiac fibroblasts versus <1% cardiac troponin T expression in AdNull (adenoviral vector that does not encode a transgene)-treated cells. Infarcted myocardium that had been treated with AdGMT likewise demonstrated greater density of cells expressing the cardiomyocyte marker beta myosin heavy chain 7 compared with AdNull-treated animals. Echocardiography demonstrated that AdGMT and LentiGMT both increased ejection fraction compared with AdNull (AdGMT: 21% ± 3%, LentiGMT: 14% ± 5%, AdNull: −0.4% ± 2%; P < .05). Conclusions Ad vectors are at least as effective as lentiviral vectors in inducing cardiac fibroblast transdifferentiation into induced cardiomyocyte-like cells and improving cardiac function in postinfarct rat hearts. Short-term expression Ad vectors may represent an important means to induce cardiac cellular reprogramming in humans.

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“…This effect was detected until 10 days after the administration, later the tumor growth depends on the effect of the therapeutic genes. It is documented that the single administration of the recombinant adenovirus to the tumor tissue favors the activation of specific immune responses, involving the recruitment and activation of inflammatory cells to viral antigens 35-37. Therefore, the activation of the immune response depends of the production of the viral antigens, which is restricted by the replication incompetent adenovirus.…”

Section: Discussionmentioning

confidence: 99%

In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer

et al. 2016

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Human papillomavirus (HPV) is a DNA virus that infects epithelial cells and has been implicated in the development of cervical cancer. Few therapeutic strategies have been designed for the treatment of cervical intraepithelial neoplasia, a precursor of cervical cancer. In these early stages, the HPV E2 protein is the most important viral factor involved in viral gene expression and plays crucial roles during the vegetative viral cycle in epithelial cells. Papillomavirus E2 binds specifically to palindromic ACCN6GGT sequences, referred to as the E2 binding sites (E2BS), which are concentrated within the viral long control region, and which are responsible for regulation of the HPV protein's expression. Here, we consider E2BS as a candidate sequence to induce the expression of antiviral therapeutic genes selectively in HPV-infected cells expressing the E2 protein. This study focuses on the use of an HPV-specific promoter comprised of four E2BS to drive the expression of IL-12, leading to an antitumor effect in an HPV-positive murine tumor model. The therapeutic strategy was implemented via viral gene therapy using adenoviral vectors with recombinant E2 and IL-12 genes and E2BS-IL-12. We demonstrate that the HPV-specific promoter E2BS is functional in vitro and in vivo through transactivation of HPV E2 transcription factor.

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Adenoviral Vector Immunity: Its Implications and Circumvention Strategies

Cited by 160 publications

References 220 publications

Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus

Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus

In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: Implications for clinical myocardial regeneration

In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer

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