Project description
Restoring immune function in chronic HIV-1 patients
Human immunodeficiency virus (HIV-1) is a global health problem with over 2 million new cases reported annually. Despite effective antiretroviral therapy, chronic patients suffer from co-morbidities due to immune dysfunction. The ERC-funded SENTINEL project aims to find novel strategies to enhance innate antiviral immunity to HIV-1 for better chronic disease control. Recent studies suggest that induction of antiviral innate immune responses in dendritic cells delays disease progression. The current paradigm suggests that HIV-1 evades innate sensing in dendritic cells leading to immune dysfunction. However, new data have revealed that HIV-1 actively suppresses an innate sensing mechanism. The objective of the current project is to test the hypothesis that drugs counteracting HIV-1 suppression will restore immune function in chronic patients.
Objective
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.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
1105AZ Amsterdam
Netherlands