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HIV-1 sensing and signaling in dendritic cells

Periodic Reporting for period 4 - SENTINEL (HIV-1 sensing and signaling in dendritic cells)

Période du rapport: 2020-04-01 au 2020-09-30

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.
We have identified the mechanism used by HIV-1 to escape activation of the immune system. We have also identified inhibitors that prevent this suppression of immune responses by HIV-1. Strikingly, we are able to revert the suppression by using the inhibitors leading to a very efficient innate and adaptive immune response. We have furthermore developed synthetic HIV-1 RNA structures that allow us to use these as adjuvants to induce adaptive immune responses. These compounds are currently under evaluation to use in as adjuvants to boost immune responses to infectious diseases. Moreover we are currently developing a clinical trial to use the identified inhibitors to enhance immunity against HIV-1 in people living with HIV-1.

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. Although the biological shredder prevents HIV-1 infection in Langerhans cells and possibly other cells, our study has also uncovered various mechanisms used by HIV-1 to escape the biological shredder. We have shown that HIV-1 uses complement system to escape the biological shredder and infect Langerhans cells. Moreover, our recent data show that HIV-1 strains that establish first infection, so called Transmitted Founder viruses, are able to escape the biological shredder in Langerhans cells. We are currently investigating the mechanism used by these specific HIV-1 strains and this will provide information on how to prevent infection by the Transmitted Founder viruses.

The findings have been disseminated by scientific publications as well as lay-man publications/interviews. Moreover we have presented our findings in various radio shows and news papers. We have obtained further funding to study the mechanisms and to bring our findings into the clinic. At scientific meetings we have presented our studies and discussed our findings with our peers.
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.
Transmitted founder HIV-1 target Langerhans cells for dissemination in the new host