A large amount of data suggest that the initial decline of HIV replication during primary HIV-1 infection is mediated by HIV-1-specific CD8+ T cells, and the investigation of immunoregulatory mechanisms that lead to the generation of these cells in primary infection is therefore of particular relevance for the understanding of protective immunity against HIV-1. Dendritic cells with professional antigen presenting properties represent a critical component of the process, and recent data suggest that their functional status is a key determinant of the ensuing HIV-1-specific CD8+ T cell responses. Yet, details about dendritic cell functions during primary infection are largely unclear, and molecular pathways regulating these cells are only at the beginning of being understood. Myelorrionocytic MHC class I receptors that are constitutionally expressed by denditic cells and monocytes represent key immunoregulatory molecules that can either stimulate or inhibit dendritic cells. Emerging data from the PL's lab indicate that these receptors can recognize peptide/MHC class I ligands in an antigenic-peptide- specific and peptide-variant-specific manner, suggesting an association between CTL-driven immune escape and altered recognition of peptide/MHC class I complexes by myelomonocytic receptors. Based on these preliminary results, we hypothesize that dendritic cells during primary HIV-1 infection represent terminally matured and effective antigen-presenting cells with strong expression of stimulatory MHC class I receptors, while their functional profile is transitioned to an immature and tolerogenic phenotype during the subsequent disease process. Moreover, we hypothesize that the formation of tolerogenic dendritic cells after primary infection is supported by early CTL escape mutations that specifically enhance binding of HIV-1 CTL epitope/MHC class I complexes to inhibitory myelomonocytic MHC class I receptors and/or reduce binding to stimulatory myelomonocytic MHC class I receptors, and that this process ultimately leads to the dysfunction of HIV-1-specific CD8+ T cells that are generated by these dendritic cells. To test these hypotheses, we will perform a phenotypic characterization of dendritic cells during primary HIV-1 infection, and systematically analyze how viral epitope diversification and early CTLdriven viral escape influences recognition by myelomonocytic MHC class I receptors and may thus alter the functional profile of dendritic cells and the ensuing HIV-1-specific CD8+ T cells. Overall, these investigations will provide key insight into the immunobiology of dendritic cells during primary HIV-1 infection, and will lead to the identification of CTL epitopes and their variants that have an immunoregulatory impact on dendritic cells via binding to meylomonocytic MHC class I receptors during primary infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI074415-04
Application #
8312518
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$539,153
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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