Final Report Summary - HIV INNATE IMMUNITY (Toward an HIV-1 vaccine:<br/>Molecular mechanisms regulating the cryptic innate immune response to HIV-1)
Innate immunity is an ancient form of defense. In humans, dendritic cells (DCs) play an important role in the control of these responses and are promising targets for therapy. Indeed, these cells have a machinery to detect pathogens that orchestrate activation of the adaptive immune system. We use HIV as model to understand the basic principle of innate immunity. We found an innate immune response against HIV exist in DCs. HIV-1 is normally not capable of infecting DCs and we use the Vpx proteins found in other lentiviruses which allows rendering DCs susceptible to HIV infection.
We have found that DC infection results in induction of an innate response, which required the interaction between a viral protein, the Capsid, and a cellular protein, Cyclophilin A. Engaging this response leads to production of type I interferon, activation of adaptive immunity and blocking of T cell infection by the virus. We hypothesized that the innate response, which is cryptic because normally absent without efficient infection of DCs, is a factor that determines the ability of the immune system to control HIV infection. Based on these results, we aim at understanding how the interaction between Capsid and Cyclophilin A is connected to the cellular machinery that controls innate immune responses.
During the course of the project, we have identified a mechanism by which HIV-1 can be sensed. We were able to dissociate viral sensing from viral infection in dendritic cells. Doing so, we obtained a modified virus that allowed us to determine the viral determinants of sensing by dendritic cells. We have identified that the viral cDNA is essential for sensing and that in the cell, the innate sensor cGAS is required for detecting HIV-1. This work has been published in the journal Immunity. In addition to this, we have identified a novel regulator of HIV sensing in DCs. We are currently studying how this factor function in dendritic cells. Importantly these results inform us on how the innate immune system might sense HIV, and how the virus escapes this sensing.
We have found that DC infection results in induction of an innate response, which required the interaction between a viral protein, the Capsid, and a cellular protein, Cyclophilin A. Engaging this response leads to production of type I interferon, activation of adaptive immunity and blocking of T cell infection by the virus. We hypothesized that the innate response, which is cryptic because normally absent without efficient infection of DCs, is a factor that determines the ability of the immune system to control HIV infection. Based on these results, we aim at understanding how the interaction between Capsid and Cyclophilin A is connected to the cellular machinery that controls innate immune responses.
During the course of the project, we have identified a mechanism by which HIV-1 can be sensed. We were able to dissociate viral sensing from viral infection in dendritic cells. Doing so, we obtained a modified virus that allowed us to determine the viral determinants of sensing by dendritic cells. We have identified that the viral cDNA is essential for sensing and that in the cell, the innate sensor cGAS is required for detecting HIV-1. This work has been published in the journal Immunity. In addition to this, we have identified a novel regulator of HIV sensing in DCs. We are currently studying how this factor function in dendritic cells. Importantly these results inform us on how the innate immune system might sense HIV, and how the virus escapes this sensing.