Descrizione del progetto
Ripristinare la funzione immunitaria in pazienti cronici affetti da HIV-1
Il virus dell’immunodeficienza umana di tipo 1 (HIV-1) è un problema di salute globale, con oltre 2 milioni di nuovi casi segnalati ogni anno. Nonostante l’efficacia della terapia antiretrovirale, i pazienti cronici soffrono di comorbidità dovute a disfunzioni immunitarie. Il progetto SENTINEL, finanziato dal CER, intende trovare nuove strategie per potenziare l’immunità antivirale innata contro l’HIV-1 per un migliore controllo della malattia cronica. Studi recenti suggeriscono che l’induzione di risposte immunitarie innate antivirali nelle cellule dendritiche ritardi la progressione della malattia. Il paradigma attuale suggerisce che l’HIV-1 elude il rilevamento innato nelle cellule dendritiche, portando a disfunzioni immunitarie. Tuttavia, nuovi dati hanno rivelato che l’HIV-1 sopprime attivamente un meccanismo di rilevamento innato. L’obiettivo del progetto attuale è quello di verificare l’ipotesi secondo cui i farmaci che contrastano la soppressione dell’HIV-1 ripristinerebbero la funzione immunitaria nei pazienti cronici.
Obiettivo
HIV-1 is a major global health problem with over 2 million new infections every year, and although antiretroviral therapy is effective, chronic infected patients suffer from severe co-morbidities due to immune dysfunction. With the proposed SENTINEL project, I aim to identify novel strategies to enhance innate antiviral immunity to HIV-1 to limit establishment and progression of chronic disease. Our novel data strongly suggest that induction of antiviral innate immune responses in dendritic cell subsets delays disease progression and improves survival in chronic HIV-1-infected patients. Current paradigm suggests that HIV-1 evades innate sensing in dendritic cells and that this underlies immune dysfunction. However, our innovative data demonstrate that HIV-1 actively suppresses a novel innate sensing mechanism and antagonizing this HIV-1 suppression by drugs strongly enhanced antiviral immunity. Strikingly, we identified a gene polymorphism in a component of the novel HIV-1 sensing machinery, rendering the pathway insensitive to HIV-1 suppression; this polymorphism is associated with delayed disease progression and improved survival in HIV-1 patients from the Amsterdam Cohort Studies. Thus, I hypothesize that therapies counteracting the suppression by HIV-1 will enhance antiviral immunity and restore immune dysfunction in chronic patients. Within this SENTINEL project, novel targets for HIV-1 therapy will be identified. As we identified proto-oncogenes involved in the suppression of innate immune responses by HIV-1, we will also screen clinically approved anti-cancer drugs as novel therapies to enhance the innate immune responses to HIV-1. Our exciting data strongly underscore the innovation and feasibility of the project. The unique expertise of my group in elucidating complex mechanisms that shape immunity, our innovative ex vivo human tissue infection models and cohort studies will be crucial in the proposed research and paramount to its success.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
1105AZ Amsterdam
Paesi Bassi