Oncotarget

Research Papers:

Native and engineered tropism of vectors derived from a rare species D adenovirus serotype 43

Natalya Belousova, Galina Mikheeva, Chiyi Xiong, Loren J. Stagg, Mihai Gagea, Patricia S. Fox, Roland L. Bassett, John E. Ladbury, Michael B. Braun, Thilo Stehle, Chun Li and Victor Krasnykh _

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Oncotarget. 2016; 7:53414-53429. https://doi.org/10.18632/oncotarget.10800

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Abstract

Natalya Belousova1, Galina Mikheeva1, Chiyi Xiong1, Loren J. Stagg2,5, Mihai Gagea3, Patricia S. Fox4, Roland L. Bassett4, John E. Ladbury2,5,6,8, Michael B. Braun7, Thilo Stehle7, Chun Li1,6, Victor Krasnykh1,6

1Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

5Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

6The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

7Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany

8Current address: University of Leeds, Leeds, United Kingdom

Correspondence to:

Victor Krasnykh, email: vkrasnykh@mdanderson.org

Keywords: adenovirus, serotype, tropism, CD46, targeting

Received: June 15, 2016     Accepted: July 13, 2016     Published: July 23, 2016

ABSTRACT

Unique molecular properties of species D adenoviruses (Ads)—the most diverse yet underexplored group of Ads—have been used to develop improved gene vectors. The low seroprevalence in humans of adenovirus serotype 43 (Ad43), an otherwise unstudied species D Ad, identified this rare serotype as an attractive new human gene therapy vector platform. Thus, in this study we wished to assess biological properties of Ad43 essential to its vectorization. We found that (1) Ad43 virions do not bind blood coagulation factor X and cause low random transduction upon vascular delivery; (2) they clear host tissues more quickly than do traditionally used Ad5 vectors; (3) Ad43 uses CD46 as primary receptor; (4) Ad43 can use integrins as alternative primary receptors. As the first step toward vectorization of Ad43, we demonstrated that the primary receptor specificity of the Ad43 fiber can be altered to achieve infection via Her2, an established oncotarget. Whereas this modification required use of the Ad5 fiber shaft, the presence of this domain in chimeric virions did not make them susceptible for neutralization by anti-Ad5 antibodies.


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