Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - SENTINEL (HIV-1 sensing and signaling in dendritic cells)
Teaser
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...
Summary
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 individuals. 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 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 lower virus replication in HIV-1 infected individuals from the Amsterdam Cohort Studies. Thus, we will develop therapies counteracting the suppression by HIV-1 to enhance antiviral immunity and restore immune function in chronic patients.
Moreover, we have identified a novel restriction mechanism in specific immune cells that prevent HIV-1 infection. Our data show that these specific immune cells, called Langerhans cells, capture HIV-1 and route HIV-1 into a so-called biological shredder, which results in the destruction of the virus. Even though all cells have this biological shredder, it only works in Langerhans cells because of a specific protein. We were able to introduce this protein in other cells, which made these cells resistent to HIV-1 as the biological shredder was able to destroy the virus. Thus, targeting this biological shredder in HIV-1 infected individuals might limit HIV-1 infected individuals and we are currently investigating whether drugs can be used to activate this shredder.
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. These findings are important for high risk populations as well as HIV-1 infected individuals, as we aim to develop novel strategies to counteract HIV-1 infection and pathogenesis.
Work performed
We have set out to identify molecular mechanisms that either facilitate HIV-1 infection or prevent HIV- infection. We have identified a novel mechanism that is used by HIV-1 to escape antiviral immunity. We have developed methods to block this evasion strategy, which led to decreased HIV-1 replication as well as increased antiviral immunity. Furthermore, we have identified a specific sensor for HIV-1 that detects HIV-1 replication and induces a strong efficient antiviral immune response. Targeting this sensor induces very efficient antiviral immune responses. We are currently developing tools to trigger this sensor during vaccinations.
We have also identified the mechanism that restricts HIV-1 infection and we were able to identify in a specific immune cell, called Langerhans cells, a biological shredder that destroys HIV-1. Not only have we identified the biological shredder but we were also able to activate the shredder in other cells and thereby render these cells resistant to HIV-1 infection. We are currently investigating whether we can develop tools to enhance the biological shredder in HIV-1 infected individuals.
Final results
We have obtained very innovative results on the sensing mechanisms in immune cells for HIV-1. We identified a ubiquitous expressed sensor for HIV-1 that can be triggered to activate antiviral immune responses and limit HIV-1 replication. We will further investigate the function of this sensor and how we can harness its activity to induce antiviral immunity upon HIV-1 infection.
Moreover, we have identified a biological shredder that is present in all immune cells but is only able to destroy HIV-1 in specific immune cells, called Langerhans cells. Strikingly, we have identfied the mechanism that controls this shredder in Langerhans cells, and we have developed a genetic method to also activate the shredder in other cells to destroy HIV-1. We are now investigating whether drugs are also able to enhance this biological shredder in the other cells, which would provide protection against HIV-1.