Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering.

Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing α and ß defensins from humans has demonstrated that the α-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are θ-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype θ-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes.

RCSB Protein Data Bank tools for 3D structure-guided cancer research: human papillomavirus (HPV) case study.

Atomic-level three-dimensional (3D) structure data for biological macromolecules often prove critical to dissecting and understanding the precise mechanisms of action of cancer-related proteins and their diverse roles in oncogenic transformation, proliferation, and metastasis. They are also used extensively to identify potentially druggable targets and facilitate discovery and development of both small-molecule and biologic drugs that are today benefiting individuals diagnosed with cancer around the world. 3D structures of biomolecules (including proteins, DNA, RNA, and their complexes with one another, drugs, and other small molecules) are freely distributed by the open-access Protein Data Bank (PDB). This global data repository is used by millions of scientists and educators working in the areas of drug discovery, vaccine design, and biomedical and biotechnology research. The US Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) provides an integrated portal to the PDB archive that streamlines access for millions of worldwide PDB data consumers worldwide. Herein, we review online resources made available free of charge by the RCSB PDB to basic and applied researchers, healthcare providers, educators and their students, patients and their families, and the curious public. We exemplify the value of understanding cancer-related proteins in 3D with a case study focused on human papillomavirus.

[Human papilloma virus and cervical cancer. An historical review on the development of research on cancer of the cervix uteri in Venezuela]. / El virus del papiloma humano y el cáncer cervical. Una revisión de la historia actualizada sobre la investigación del cáncer del cuello uterino en Venezuela.

The history on the relationship of VPH infection and cervical cancer was examined. Findings were initially reported in Maracaibo(1971), later in Mexico(1973) and thereafter several studies on the ultrastructure and immunohistochemistry of VPH infection and its role on cervical cancer were described. The ultrastructural findings of viral particles of HPV and their proteins, as well as their role in the incorporation of the viral genome to the human cervical cells were also described. Glycoproteins on the surface of cervical cells were reviewed and their importance on HPV infection was related to p16, blood group antigens and early genetic changes in the cell cycle with loss of heterozigocity, all of which, stimulated by the high risk HPV infection lead to cervical cancer.

Papillomavirus prophylactic vaccines: established successes, new approaches.

Vaccines against the human papillomaviruses (HPVs) most frequently associated with cancer of the cervix are now available. These prophylactic vaccines, based on virus-like particles (VLPs), are extremely effective, providing protection from infection in almost 100% of cases. However, the vaccines present some limitations: they are effective primarily against the HPV type present in the vaccine, are expensive to produce, and need a cold chain. Vaccines based on the minor capsid protein L2 have been very successful in animal models and have been shown to provide a good level of protection against different papillomavirus types. The potential of L2-based vaccines to protect against many types of HPVs is discussed.

[Construction of prophylactic recombinant HPV58-attenuated Shigella vector live vaccine and evaluation of its protective efficacy and immunogenicity in the guinea pig keratoconjunctivitis model].

AIM: To construct the prophylactic recombinant HPV58-attenuated Shigella vector live vaccine and evaluate its protective efficacy and immunogenicity in the Guinea pig Keratoconjunctivitis model. METHODS: The HPV58 L1 gene was cloned into PUCMT, and the recombinant plasmid HPV58 L1-pCVD442 was constructed and introduced into attenuated Shigella (Sf301: deltavirG) with helper plasmid PRK2013 by filter mating. After homologous recombination, the positive colonies in Sf301: deltavirG strains contained HPV58L1 gene were selected and verified by PCR. The expressed HPV58L1 protein was harvested and analyzed by SDS-PAGE and Western blot. The bio-activity of the interested protein was identified by mouse erythrocyte hemagglutination assay, and the VLP formation was proved with transmission electron microscope. Guinea pig Keratoconjunctivitis model was used to evaluate protective efficacy and immunogenicity of the vaccine. 20 days after immunization, serum HPV58L1-IgG, IgA level and serum sf301 LPS- IgG, IgA level were measured by ELISA, and HPV58 L1-specific IgA-ASC and IgG-ASC of spleen and lymph nodes (SVCLN, MDLN, MSLN and pp) were measured by ELISPOT assay. RESULTS: HPV58 L1 protein with MW 60 kDa was confirmed by Western blot. The ability of the interested protein to self-assemble into VLPs was identified by transmission electron microscope, and the result of murine erythrocyte hemagglutination assay indicated that the given proteins expressed by the recombinant bacillus had similar characteristics as the natural HPV58L1 protein.In the Guinea pig Keratoconjunctivitis Model, animal immune results showed that there were no Keratoconjunctivitis occurred in the immune group(HPV58-attenuated Shigella), and after Sf301 attacking, 80% eyes had no Keratoconjunctivitis occurrence. 20 days after immunization, serum HPV58L1-IgG, IgA level were obviously increased; but serum sf301 LPS-IgG position was just slightly increased; ELISPOT results showed that HPV58 L1-specific IgA-ASC and IgG-ASC of spleen and lymph nodes were also obviously increased. CONCLUSION: Recombinant HPV58L1-attenuated Shigella vector live vaccine could induce strong humoral immune responses in the immunized animals.