Advances in the development of new prophylactic and therapeutic vaccines against Human Papillomavirus

Prophylactic vaccines against high risk HPV has become important because of the high oncogenic potential of the virus and its association with cervical cancer development, one of the most common and fatal cancers among women worldwide. The objective of this article is describe the state of the art of the current prophylactic and therapeutic HPV vaccines, analyzing their characteristics, advantages, disadvantages and scientific reports on its use and safety in the population. A systematic revision of the latest advances in the development of prophylactic and therapeutic vaccines against HPV was performed. Prophylactic vaccination is effective and essential for the prevention of uterine cervical cancer; new therapeutic vaccines have been shown at the initial phases to be promising contributing in the regression of premalignant or malignant in situ lesions.El uso de vacunas proilácticas contra el Virus del Papiloma Humano (VPH) de alto riesgo ha adquirido gran importancia debido al alto potencial oncogénico, de estos virus, especialmente por su asociación con el cáncer de cuello uterino, uno de los canceres más comunes y de mayor mortalidad en mujeres a nivel mundial. El objetivo de este artículo es describir las vacunas proilácticas y terapéuticas disponibles actualmente contra el VPH, analizando las características, ventajas, desventajas y estudios cientíicos sobre su uso y seguridad en la población. Se llevó a cabo una revisión de literatura de los últimos avances en el desarrollo de vacunas proilácticas y terapéuticas contra el VPH. La vacunación proiláctica es efectiva y esencial para la prevención del cáncer de cuello uterino causadas por VPH-16 y -18, pero no genera protección cruzada contra otros VPH de alto riesgo, esto ha encaminado a la creación de nuevas vacunas nanovalentes que protegen contra un número mas amplio de VPHs de alto riesgo. Por otra parte, las vacunas terapéuticas han demostrado en sus fases de estudio iniciales ser promisorias en la regresión de lesiones premalignas o malignas in situ

Regulation of MCP-1 chemokine transcription by p53

<p>Abstract</p> <p>Background</p> <p>Our previous studies showed that the expression of the monocyte-chemoattractant protein (MCP)-1, a chemokine, which triggers the infiltration and activation of cells of the monocyte-macrophage lineage, is abrogated in human papillomavirus (HPV)-positive premalignant and malignant cells. <it>In silico </it>analysis of the MCP-1 upstream region proposed a putative p53 binding side about 2.5 kb upstream of the transcriptional start. The aim of this study is to monitor a physiological role of p53 in this process.</p> <p>Results</p> <p>The proposed p53 binding side could be confirmed <it>in vitro </it>by electrophoretic-mobility-shift assays and <it>in vivo </it>by chromatin immunoprecipitation. Moreover, the availability of p53 is apparently important for chemokine regulation, since TNF-α can induce MCP-1 only in human keratinocytes expressing the viral oncoprotein E7, but not in HPV16 E6 positive cells, where p53 becomes degraded. A general physiological role of p53 in MCP-1 regulation was further substantiated in HPV-negative cells harboring a temperature-sensitive mutant of p53 and in Li-Fraumeni cells, carrying a germ-line mutation of p53. In both cases, non-functional p53 leads to diminished MCP-1 transcription upon TNF-α treatment. In addition, siRNA directed against p53 decreased MCP-1 transcription after TNF-α addition, directly confirming a crosstalk between p53 and MCP-1.</p> <p>Conclusion</p> <p>These data support the concept that p53 inactivation during carcinogenesis also affects immune surveillance by interfering with chemokine expression and in turn communication with cells of the immunological compartment.</p

Avances en el desarrollo de nuevas vacunas profilácticas y terapéuticas contra el Virus del Papiloma Humano

El uso de vacunas proilácticas contra el Virus del Papiloma Humano (VPH) de alto riesgo ha adquirido gran importancia debido al alto potencial oncogénico, de estos virus, especialmente por su asociación con el cáncer de cuello uterino, uno de los canceres más comunes y de mayor mortalidad en mujeres a nivel mundial. El objetivo de este artículo es describir las vacunas proilácticas y terapéuticas disponibles actualmente contra el VPH, analizando las características, ventajas, desventajas y estudios cientíicos sobre su uso y seguridad en la población. Se llevó a cabo una revisión de literatura de los últimos avances en el desarrollo de vacunas proilácticas y terapéuticas contra el VPH. La vacunación proiláctica es efectiva y esencial para la prevención del cáncer de cuello uterino causadas por VPH-16 y -18, pero no genera protección cruzada contra otros VPH de alto riesgo, esto ha encaminado a la creación de nuevas vacunas nanovalentes que protegen contra un número mas amplio de VPHs de alto riesgo. Por otra parte, las vacunas terapéuticas han demostrado en sus fases de estudio iniciales ser promisorias en la regresión de lesiones premalignas o malignas in situ.Prophylactic vaccines against high risk HPV has become important because of the high oncogenic potential of the virus and its association with cervical cancer development, one of the most common and fatal cancers among women&nbsp;worldwide. The objective of this article is describe the state of the art of the current prophylactic and therapeutic HPV vaccines, analyzing their characteristics, advantages, disadvantages and scientific reports on its use and safety in the population. A systematic revision of the latest advances in the development of prophylactic and therapeutic vaccines against HPV was performed. Prophylactic vaccination is effective and essential for the prevention of uterine cervical cancer; new therapeutic vaccines have been shown at the initial phases to be promising contributing in the regression of premalignant or malignant in situ lesions

Detection of high-risk Human Papilloma Virus type 16 and 18 using Isothermal Helicase-Dependent Amplification

Persistent infection with human papillomavirus (HPV) induces cervical cancer. Here, we describe a sensitive, specific, and rapid assay for high-risk HPV16 and 18 detection by isothermal helicase-dependent amplification. This method can be used as cost-effective diagnostic method for low-income countries, where highest incidences worldwide of cervical cancer are registered

Regulation of MCP-1 chemokine transcription by p53. Mol Cancer 9

Abstract Background: Our previous studies showed that the expression of the monocyte

Repurposing of Four Drugs as Anti-SARS-CoV-2 Agents and Their Interactions with Protein Targets

Although there are existing vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), new COVID-19 cases are increasing due to low immunization coverage and the emergence of new variants. For this reason, new drugs to treat and prevent severe COVID-19 are needed. Here, we provide four different FDA-approved drugs against SARS-CoV-2 proteins involved in the entry and replication process, aiming to identify potential drugs to treat COVID-19. We use the main protease (Mpro), the spike glycoprotein (S protein), and RNA-dependent RNA polymerase (RdRp) as protein targets for anti- SARS-CoV-2 drugs. In our constructed database, we selected different drugs against each target (Mpro, S protein, and RdRp) based on their common interactions with relevant residues involved in viral entry at the host cell and replication. Furthermore, their stability inside the binding pocket, as well as their predicted binding-free energy, allow us to provide new insight into the possible drug repurposing of viomycin (interacting with Mpro) due to its interactions with key residues, such as Asn 143, Glu 166, and Gln 189 at the same time as hesperidin (interacting with the S protein) is interacting with residues Tyr 449, Ser 494, and Thr 500, keeping inside the predicted binding pocket, as well as interacting with residues in different variants of concern. Finally, we also suggest nystatin and elvitegravir (interacting with RdRp) as possible drugs due to their stability within the predicted pocket along the simulation and their interaction with key residues, such as Asp 760, Asp 761, and Asp 618. Altogether our results provide new knowledge about the possible mechanism of the inhibition of viomycin, hesperidin, elvitegravir, and nystatin to inhibit the viral life cycle of SARS-CoV-2 and some of its variants of concern (VOC). Additionally, some iodide-based contrast agents were also found to bind the S protein strongly, i.e., iohexol (−58.99 Kcal/mol), iotrolan (−76.19 Kcal/mol), and ioxilan (−62.37 Kcal/mol). Despite the information we report here as the possible strong interaction between these contrast agents and the SARS-CoV-2′s S protein, Mpro, and RdRp, we believe that further investigation, including chemical modifications in their structures, are needed for COVID-19 treatment

Post-translational control of IL-1β via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53.

Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1β) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1β production is tightly controlled on transcriptional, post-translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1β processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1β regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1β was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1β that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1β is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1β levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1β regulation which ultimately inhibits the secretion of IL-1β in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV-positive tissue samples, where a gradual decrease of IL-1β towards cervical cancer could be discerned. Hence, attenuation of IL-1β by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy