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

Descrizione del progetto

Dissezione dell’ingresso cellulare degli herpesvirus

Gli herpesvirus sono virus a DNA che provocano infezioni ad alta incidenza e che durano tutta la vita, rappresentando una seria criticità dal punto di vista sanitario. Per prevenire le malattie associate agli herpesvirus, è necessario individuare rapidamente nuovi farmaci antivirali. Finanziato dal programma di azioni Marie Skłodowska-Curie, il progetto HSV1ENTRYPROTEINMAP mira a studiare il meccanismo di ingresso degli herpesvirus nelle cellule. I ricercatori si avvarranno di un approccio multidisciplinare per delineare la disposizione delle glicoproteine virali e la loro interazione con i partner cellulari per mediare la fusione dell’involucro virale con la membrana cellulare. I risultati contribuiranno a risolvere il problema della trasmissione degli herpesvirus, nella speranza di facilitare la progettazione di vaccini.

Obiettivo

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.