ssDNA virus evolution, pathogenesis and anti-cancer potential

Research summary:

We investigate the molecular biology of ssDNA viruses, with special emphasis in virus members of the Parvoviridae, to understand their evolution patterns, mechanisms underlying pathogenicity, and oncolytic potential against human cancer.

In pathogenicity studies, we combine mice infections with sequence analysis of the parvovirus Minute Virus of Mice (MVM) genetic variants arising at precise stages of the diseases. The evolutionary capacity of this virus in response to immune and adaptive pressures is monitored by genome sequencing and localization of the selected amino acid changes in defined functional domains of the capsid 3-D structure (Figure 1).

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Figure 1. A. Localization of Mab-resistant mutations in the parvovirus MVMi capsid. B. A constellation of proximal residues at the 2fold axis of the MVM capsid contributes to the hemopoietic disease caused by the virus in scid mouse.

The oncolytic capacity of MVM is being addressed by an in-depth analysis of the virus life cycle steps in human cancer cells aimed at identifying regulators and precise molecular interactions at each major virus life cycle stage (Figure 2). For example, capsid assembly proceeds as trimeric intermediates that translocate through the nuclear envelope at the S phase of the cell cycle. Their nuclear transport competence relies on the phosphorylation levels of the protein subunits mediated by kinases deregulated in cancer cells (Figure 3 and 4).

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Figure 2. Major steps in the parvovirus MVM life cycle.

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Figure 3. Time and functional coupling between cell cycle and parvovirus nuclear assembly. This coupling is relevant for understanding parvovirus pathogenesis and oncotropism, and its disturbance may determine viral persistence in tissues.

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Figure 4. Phosphorylation of the VP2 and VP1 capsid subunits by the Raf-1 kinase (MAPK) drives their trimeric oligomerization, S phase nuclear translocation and capsid assembly.

Capsid engineering. Other simultaneous efforts to enhance MVM oncolysis tackle re-targeting the virus to the neovascularization process required for tumor growth. We are engineering different domains of MVM capsid with heterologous peptides blocking VEGF, either to induce antibodies that may reduce tumor growth, or to drive the tropism of the virus specifically to VEGF-R expressing vascular cells supporting the tumor vascularization (Figure 5).

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Figure 5. The four loops configuring the spike at the 3fold axis of the MVM capsid. Right, residues of the loop 4 substituted by engineered VEGF-blocking peptides.

Metagenomic studies. In recent years we have also been interested in understanding viral assemblages in natural environments and animals. By using metagenomics we have genetically identified a second subfamily of papillomavirus as well as new human members of the families Anelloviridae, Papillomaviridae y Redondoviridae. Currently, we are using NGS to investigate the main sources of bias introduced during the preparation of human viromes. We are also conducting the largest metagenomic survey of viruses in the human mouth to date. Most of the 400 nearly full-length genomes already assembled from these viromes belong to new bacteriophages whose host-interactions are being predicted by various bioinformatic approaches (Figure 6).

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Figure 6. Host prediction at phyla level (colors) for a sequence similarity network of ~1,500 viral contigs de novo assembled from 35 human oral viromes.

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* For external calls please dial 34 91196 followed by the extension number
Last name Name Laboratory Ext.* e-mail Professional category
Almendral del Río José Mª 224 4559 jmalmendral(at)cbm.csic.es Catedrático Universidad, GA
López-Bueno Alberto 224 4589 alopezbueno@cbm.csic.es Profesor Contratado Universidad, GA

Relevant publications:

  • Lopez-Bueno, A., Segovia, J.C., Bueren, J.A., O´Sullivan, G., Tattersall, P., and J.M. Almendral. 2008. Evolution to pathogenicity of the parvovirus MVM in immunodeficient mice involves genetic heterogeneity at the capsid domain that determines tropism. J. Virol. 82, 1195-1203. Doi: 10.1128/JVI.01692-07.
  • López-Bueno A, Tamames J, Velázquez D, Moya A, Quesada A, and A. Alcamí. 2009. High diversity of the viral community from an Antarctic lake. Science. 6;326(5954):858-61. Doi: 10.1126/science.1179287.
  • Riolobos, L., Valle, N., Hernando, E., Maroto, B., Kann, M., and J.M. Almendral. 2010. Viral oncolysis that targets Raf-1 signalling control of nuclear transport. J. Virol. 84, 2090-2099. Doi: 10.1128/JVI.01550-09.
  • Gil-Ranedo, J., Hernando, E., Riolobos, L., Domínguez, C., Kann, M., and J.M. Almendral. 2015. The mammalian cell cycle regulates parvovirus nuclear capsid assembly. Plos Pathogens. 11;11(6):e1004920. Doi: 10.1371/journal.ppat.1004920.
  • López-Bueno A., Rastrojo A., Peiró R., Arenas M., and A. Alcamí. 2015. Ecological connectivity shapes quasispecies structure of RNA viruses in an Antarctic lake. Mol. Ecol. 24(19):4812-25. Doi: 10.1111/mec.13321. Cover of the Journal.
  • López-Bueno A., Mavian C., Labella A.M., Castro D., Borrego J.J., Alcami A., and A. Alejo. 2016. Concurrence of Iridovirus, Polyomavirus, and a Unique Member of a New Group of Fish Papillomaviruses in Lymphocystis Disease-Affected Gilthead Sea Bream. J. Virol. 12;90(19):8768-79. Doi: 10.1128/JVI.01369-16.
  • Ros, C., Bayat N., Wolfisberg R., and J.M. Almendral. 2017. Protoparvovirus Cell Entry. Viruses. 9, 313. Doi: 10.3390/v9110313.
  • Gil-Ranedo J., Hernando E., Valle N., Riolobos L., Maroto B., and J.M. Almendral. 2018. Differential phosphorylation and n-terminal configuration of capsid subunits in parvovirus assembly. Virology. 518, 184–194. Doi: org/10.1016/j.virol.2018.02.018.
  • Parras-Moltó M., Rodríguez-Galet A., Suárez-Rodríguez P., and A. López-Bueno. 2018. Evaluation of bias induced by viral enrichment and random amplification protocols in metagenomic surveys of saliva DNA viruses. Microbiome. 28;6(1):11. Doi: 10.1186/s40168-018-0507-3.
  • Grueso, E.C., Sánchez-Martínez T., Calvo-López F.J., de Miguel N., Blanco-Menéndez M., Fernández-Estévez M., Elizalde J., Sánchez O., Kourani D., Martin A., Tato M., Guerra S., Andrés G., and J.M. Almendral. 2019. Antiangiogenic VEGF-Blocking Peptides Displayed on the Capsid of an Infectious Oncolytic Parvovirus: Assembly and Immune Interactions. J. Virol. 93, Issue 19 e00798-19. Doi: 10.1128/JVI.00798-19.

Doctoral theses:

  • Nooshin Bayat (2018). Modificaciones de la cápsida de parvovirus en la entrada de células de cancer e invasión evolutiva de genomas de primates/Parvovirus capsid modifications in cancer cell entry and evolutionary invasion of primate genomes. Director: José María Almendral del Río.
  • Marcos Parras Moltó (2019). “Estudio metagenómico de la comunidad de virus y de su interacción con la microbiota en la cavidad bucal humana”. Director: Alberto López Bueno.

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