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      Development of Novel Adenoviral Vectors to Overcome Challenges Observed With HAdV-5–based Constructs

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          Abstract

          Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in preclinical models and clinical trials over the past two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread preexisting immunity have been shown to significantly impede the effectiveness of HAdV-5–mediated gene transfer. It is therefore that the in-depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes.

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          Most cited references173

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          Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5.

          A complementary DNA clone has been isolated that encodes a coxsackievirus and adenovirus receptor (CAR). When transfected with CAR complementary DNA, nonpermissive hamster cells became susceptible to coxsackie B virus attachment and infection. Furthermore, consistent with previous studies demonstrating that adenovirus infection depends on attachment of a viral fiber to the target cell, CAR-transfected hamster cells bound adenovirus in a fiber-dependent fashion and showed a 100-fold increase in susceptibility to virus-mediated gene transfer. Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
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            International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations.

            Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×10(10)vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Atomic structure of human adenovirus by cryo-EM reveals interactions among protein networks.

              Construction of a complex virus may involve a hierarchy of assembly elements. Here, we report the structure of the whole human adenovirus virion at 3.6 angstroms resolution by cryo-electron microscopy (cryo-EM), revealing in situ atomic models of three minor capsid proteins (IIIa, VIII, and IX), extensions of the (penton base and hexon) major capsid proteins, and interactions within three protein-protein networks. One network is mediated by protein IIIa at the vertices, within group-of-six (GOS) tiles--a penton base and its five surrounding hexons. Another is mediated by ropes (protein IX) that lash hexons together to form group-of-nine (GON) tiles and bind GONs to GONs. The third, mediated by IIIa and VIII, binds each GOS to five surrounding GONs. Optimization of adenovirus for cancer and gene therapy could target these networks.
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                Author and article information

                Journal
                Mol Ther
                Mol. Ther
                Molecular Therapy
                Nature Publishing Group
                1525-0016
                1525-0024
                February 2016
                19 October 2015
                24 November 2015
                1 February 2016
                : 24
                : 1
                : 6-16
                Affiliations
                [1 ]Institute of Cardiovascular and Medical Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow , Glasgow, UK
                [2 ]Institute for Veterinary Medical Research, Centre for Agricultural Research, Hungarian Academy of Sciences , Budapest, Hungary
                [3 ]Batavia Biosciences B.V. , Leiden, The Netherlands
                [4 ]Current address: Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh , Edinburgh, UK
                Author notes
                [* ]Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Little France Crescent, Edinburgh, UK. E-mail: andy.Baker@ 123456ed.ac.uk
                Article
                mt2015194
                10.1038/mt.2015.194
                4754553
                26478249
                68517f94-2c40-485f-8926-5ca3d17e349f
                Copyright © 2016 American Society of Gene & Cell Therapy

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 14 September 2015
                : 07 October 2015
                Categories
                Review

                Molecular medicine
                Molecular medicine

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