Development of a memory immune response to virus infection is a critical step in the eventual control of these infections. Presence of virus-specific CD4+ T cells during the primary immune response to a virus pathogen appears to be a determining factor in whether an effective CD8 effector response is elicited. In HIV infection, where the main viral targets are HIV-specific CD4+ T ceils, the consequences for development of an effective memory are likely central for pathogenesis. In this proposal we will examine host-viral interactions occurring in the acute/early disease infection phase of HIV in 2 groups of untreated HIV infected individuals, those who do versus those who do not efficiently control viremia. Autologous plasma virus replicating before seroconversion and at a time point six month later will be completely sequenced. Variations in sequence between the original autologous virus and viral sequences used to make reference HIV peptide sets will be identified as will changes from the original autologous isolate in virus present 6 months later. Peptides spanning these variations from reference peptide sets will be synthesized. Reference and autologous peptide libraries will be used to screen lymphocytes for HIV-specific immune responses mediated by both CD4+ and CD8+ T cells using EL1SPOT and multi-parametric FACS analyses to detect antigen-specific cells that proliferate, secrete IL-2 and/or secrete IFN-.. This will survey the true breadth, magnitude and specificity of HIV-specific immunity to autologous virus and how the frequency and function of these cells changes with time to epitopes that do or do not mutate to escape immune recognition. Selected responses will be followed using tetrameric reagents to mark antigen specific cells, and phenotypic markers will be used to identify memory cells subsets and markers for function. These analyses will address the relationship between viral control and the distribution of epitope-specific CD4+ and CD8+ memory subsets in order to determine whether skewed distribution or blockage in memory cell differentiation occurs more frequently for epitopes that escape viral control compared to those that do not. Overall, we will be able to assess the importance of Ag specific CD4+ memory T cells and of viral escape in the maintenance of persistence CTL response. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043261-06
Application #
7058199
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Wassef, Nabila M
Project Start
1999-09-30
Project End
2007-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$388,341
Indirect Cost
Name
University of Montreal
Department
Type
DUNS #
207622838
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 3-J7
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