An extension of the Minute Virus of Mice tissue tropism

Etingov, Igor; Itah, Refael; Mincberg, Michal; Keren-Naus, Ayelet; Nam, Hyun Joo; Agbandje‐McKenna, Mavis; Davis, Claytus

doi:10.1016/j.virol.2008.06.042

Cited by 6 publications

(4 citation statements)

References 51 publications

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“…An MVMp host range switch mutant, MVMp-F1, that adapted in tissue culture to replicate in rat fibroblasts, which are normally nonpermissive to MVM, contains mutations at VP2 amino acid residues A334T, E384A, N554D, and I578L (67). The structurally equivalent residues in H-1PV, A340, E390, V560, and I584 are located in VR4a (A340), VR6 (E390), and VR8 (V560), which surround the 2-fold depression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural Characterization of H-1 Parvovirus: Comparison of Infectious Virions to Empty Capsids

Halder

Nam

Govindasamy

et al. 2013

J Virol

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bThe structure of single-stranded DNA (ssDNA) packaging H-1 parvovirus (H-1PV), which is being developed as an antitumor gene delivery vector, has been determined for wild-type (wt) virions and noninfectious (empty) capsids to 2.7-and 3.2-Å resolution, respectively, using X-ray crystallography. The capsid viral protein (VP) structure consists of an ␣-helix and an eightstranded anti-parallel ␤-barrel with large loop regions between the strands. The ␤-barrel and loops form the capsid core and surface, respectively. In the wt structure, 600 nucleotides are ordered in an interior DNA binding pocket of the capsid. This accounts for ϳ12% of the H-1PV genome. The wt structure is identical to the empty capsid structure, except for side chain conformation variations at the nucleotide binding pocket. Comparison of the H-1PV nucleotides to those observed in canine parvovirus and minute virus of mice, two members of the genus Parvovirus, showed both similarity in structure and analogous interactions. This observation suggests a functional role, such as in capsid stability and/or ssDNA genome recognition for encapsulation. The VP structure differs from those of other parvoviruses in surface loop regions that control receptor binding, tissue tropism, pathogenicity, and antibody recognition, including VP sequences reported to determine tumor cell tropism for oncotropic rodent parvoviruses. These structures of H-1PV provide insight into structural features that dictate capsid stabilization following genome packaging and three-dimensional information applicable for rational design of tumor-targeted recombinant gene delivery vectors. H -1 parvovirus (H-1PV) is a member of the rodent subgroup of the Parvovirus genus of the single-stranded DNA (ssDNA) Parvoviridae (1). H-1PV was first isolated from rats transplanted with HEP-1, a human liver adenocarcinoma cell line (2), and also from aborted human fetuses (3). Recombinant vectors based on H-1PV and a number of other rodent parvoviruses, including minute virus of mice (MVM) and LuIII, are promising candidates for antitumor delivery vectors, particularly for cytoreductive and immunogene therapy approaches (reviewed in references 4 and 5). The inherent oncotropism of these autonomous parvoviruses is based on their dependence on cellular proliferation factors expressed during the S phase and the differentiated state of the host cell (6, 7). The rodent parvoviruses display oncopreferential cytotoxic activity in vitro and also possess an oncosuppressive potential, inhibiting the formation of spontaneous and chemical or virus-induced tumors in vitro and in vivo (8-13). These viruses can also persistently infect their natural hosts, do not integrate their genome into cellular chromosomes, and are not associated with human disease (reviewed in reference 4).Recombinant rodent parvovirus vectors targeted for tumor therapy utilize a double-edged strategy that takes advantage of their inherent oncotropism and selective cytotoxicity plus their ability to deliver therapeutic genes that code for ...

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Section: Resultsmentioning

confidence: 99%

Structural Characterization of H-1 Parvovirus: Comparison of Infectious Virions to Empty Capsids

Halder

Nam

Govindasamy

et al. 2013

J Virol

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“…Several attempts have been made to modify the natural tropism of PVs through the adaptation of the wild-type strains to specific cell types in culture (19) or through in vivo passaging (35,58). These approaches, however, lack predictability and are limited to initially semipermissive cell lines and preexisting viral tropism.…”

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confidence: 99%

Retargeting of Rat Parvovirus H-1PV to Cancer Cells through Genetic Engineering of the Viral Capsid

Allaume

El-Andaloussi

Leuchs

et al. 2012

J Virol

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The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds ␣ v ␤ 3 and ␣ v ␤ 5 integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing ␣ v ␤ 5 integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H-1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy.

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“…This has been used to retarget MPV for use in B16F10 murine melanoma by serial passaging (87), resulting in fivefold more efficient oncolysis. The prototype MVM strain MVMp has been adapted to semipermissive rat F111 fibroblasts in a similar manner (88). Directed evolution can also be applied in vivo; infection of SCID mice allowed the isolation of 40 viral clones of MVMp showing consistent amino acid substitutions in the VP gene (61).…”

Section: Capsid Modificationmentioning

confidence: 99%

A Roadmap for the Success of Oncolytic Parvovirus-Based Anticancer Therapies

et al. 2020

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Autonomous rodent protoparvoviruses (PVs) are promising anticancer agents due to their excellent safety profile, natural oncotropism, and oncosuppressive activities. Viral infection can trigger immunogenic cell death, activating the immune system against the tumor. However, the efficacy of this treatment in recent clinical trials is moderate compared with results seen in preclinical work. Various strategies have been employed to improve the anticancer activities of oncolytic PVs, including development of second-generation parvoviruses with enhanced oncolytic and immunostimulatory activities and rational combination of PVs with other therapies. Understanding the cellular factors involved in the PV life cycle is another important area of investigation. Indeed, these studies may lead to the identification of biomarkers that would allow a more personalized use of PV-based therapies. This review focuses on this work and the challenges that still need to be overcome to move PVs forward into clinical practice as an effective therapeutic option for cancer patients. Expected final online publication date for the Annual Review of Virology, Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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An extension of the Minute Virus of Mice tissue tropism

Cited by 6 publications

References 51 publications

Structural Characterization of H-1 Parvovirus: Comparison of Infectious Virions to Empty Capsids

Structural Characterization of H-1 Parvovirus: Comparison of Infectious Virions to Empty Capsids

Retargeting of Rat Parvovirus H-1PV to Cancer Cells through Genetic Engineering of the Viral Capsid

A Roadmap for the Success of Oncolytic Parvovirus-Based Anticancer Therapies

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