HIV INNATE IMMUNITY · Toward an HIV-1 vaccine:Molecular mechanisms regulating the cryptic innate immune response to HIV-1
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-10-01 → 2014-09-30
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Дендритните клетки разпознават HIV-1 чрез взаимодействие между вирусния капсид и протеина циклофилин А, което активира защитната система на организма. Разбирането на този механизъм помага при разработването на ваксина срещу вируса.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Toward an HIV-1 vaccine: 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.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Our goal is to understand the innate immune response to HIV-1. We have found that a cryptic innate immune response to HIV-1 exists in dendritic cells (DC). This response is normally inactive because HIV-1 is unable to infect DC. We have used the Vpx protein found in other lentiviruses to render DC susceptible to HIV-1 infection. The resulting innate response to HIV-1 requires an interaction between de novo synthesized Capsid and cellular Cyclophilin A. This interaction leads to the IRF-3-dependant production of type-I interferon and the activation of antigen-specific T cells. This study will aim at understanding the molecular mechanisms controlling this response.In Aim 1, we will determine the host and viral factors implicated in the innate response to HIV-1. At the host level, we will evaluate a panel of candidate genes using a novel RNAi strategy using shRNA vectors in DC. At the viral level, we will determine the minimal viral elements required for triggering the response.In Aim 2, we will identify novel regulators of the innate immune response in human DC, including the DC-specific HIV-1 innate sensor. Using a DC cDNA library, we will screen for inducers of type-I interferon in cell lines. This library will also be used to identify the Vpx-sensitive HIV-restriction factor in human DC.The cryptic nature of the innate response to HIV-1 may explain in part the failure of the immune system to control HIV-1 in the vast majority of infected individuals, as well as the failure of current vaccine strategies. This study will provide a novel understanding of the molecular mechanisms responsible for innate immune responses, and may provide new immunological strategies for controlling HIV-1 infection.
Оригинален текст от CORDIS (на английски).
Участници
- INSTITUT CURIE · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз