Spatial arrangement and interactions of HSV-1 cell entry associated proteins on the native viral envelope

Descripción del proyecto

Disección de la entrada celular de herpesvirus

Los herpesvirus son virus del ADN que causan infecciones muy frecuentes y permanentes que plantean un importante reto médico. Para prevenir las enfermedades asociadas a los herpesvirus, se necesitan de forma urgente nuevos fármacos antivirales. El equipo del proyecto HSV1ENTRYPROTEINMAP, financiado por las acciones Marie Skłodowska-Curie, tiene como objetivo investigar el mecanismo de entrada de los herpesvirus en las células. Los investigadores emplearán un método multidisciplinar para delimitar la disposición de las glicoproteínas víricas y su interacción con socios celulares a fin de mediar en la fusión de la envoltura vírica con la membrana celular. Los resultados ayudarán a abordar la transmisión del herpesvirus y posiblemente facilitarán el diseño de vacunas.

Objetivo

Herpesviruses are a family of large, complex, DNA viruses that are highly prevalent across the global human population, causing life-long infections and cycle between latent and active disease. The severity of diseases caused by this viral family ranges from cold sores, genital ulcers and blisters to blindness, meningitis, cancer, and congenital defects. Herpesviruses present a significant public health concern due to high prevalence, ease of transmission, severity of associated diseases, lack of vaccines for most species, and toxicity of available medical interventions. There remains a pressing requirement to develop novel antiviral drugs to prevent diseases associated with Herpesvirus infections. Entry of HSV-1, the focus of the proposed research, is dependent on membrane fusion mediated by virally encoded glycoproteins gB, gD, gH, and gL found on the viral envelope. Although all four glycoproteins are known to be necessary for membrane fusion, the molecular details and stoichiometry of the interactions as well as how the interactions regulate or influence the fusion process remains unknown. The proposed project aims to uncover the spatial arrangement and interactions of the HSV-1 cell entry proteins. I will employ a multidisciplinary approach combining methods and data from structural biology, biochemistry as well as biophysics to solve the mechanistic details of a virology question. The proposed research is highly innovative as it is designed to push current technological barriers by taking advantage of recent methodological advances to answer specific key biological questions in herpesvirus entry. I will determine at molecular resolution, the spatial arrangement and temporal interactions between essential entry proteins required at the onset of the HSV-1 infection. This project has the potential to unveil the detailed mechanism of action of viral glycoproteins in their native environment that ultimately lead to HSV-1 fusion.