Following viral infections, the first line of defense consists of a highly organized and aggressive innateimmune response, while the adaptive immune response, lagging behind, only develops in the context of anactive innate immunity. While we have gained extensive knowledge regarding the mechanisms thatdetermine the specificity of the adaptive immune response, very little is known about the mechanismsthat determine the recognition of HIV-1 by the innate immune response. However, not only is the innateimmune response critical in viral containment at a time when the adaptive immune response is justdeveloping, it is also critical in shaping the function of the subsequent adaptive immune response.Therefore comprehensive studies aimed at deconstructing this early critical arm of the immune response,and its relationship to the adaptive immune response, are necessary to begin to more globallyunderstand the correlates of protective immunity. Since the initial description of pattern recognitionreceptors, including Toll-like Receptors (TLRs), it has become more and more apparent that these receptorsplay a crucial role in 'sensing' viral infections and initiating the innate immune response directed at thepathogen, and we provide new data demonstrating that HIV-1 encodes for several TLR7/8 ligands.Furthermore, the main cytotoxic effector cells of the innate immune response, NK cells, can specificallyrecognize virally infected cells via a number cell-specific receptors expressed on their surface.
The aim ofthis proposal is to study the mechanisms by which the effector cells of the innate immune system,and in particular dendritic cells and NK cells, recognize HIV-1 infection and shape the function of theensuing adaptive antiviral immune response. The following specific aims will be addressed:1. Assessment of the initiation of the innate immune response by HIV-1-encoded Toll-likereceptor ligands, and the impact of innate immune activity on antiviral Tcell function.2. Determine the recognition of HIV-1-infected cells by receptors expressed on NK cells in theacute phase of infection.These studies, which will focus on the recognition of HIV-1 infection by the innate immune system, willprovide crucial new insights into HIV-1 pathogenesis, and the earliest events that occur during acute HIV-1infection that shape the adaptive immune response. The studies assessing the impact of innate immuneactivation on the quality of the ensuing adaptive virus-specific immune response will furthermore by directlyrelevant for HIV-1 vaccine design.
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