The long-term efficacy of combination antiretroviral drug therapy (HAART) for control of human immunodeficiency virus 1 (HIV-1) infection appears to require augmentation of anti-HIV-1 CD8 ? T cell responses using immunotherapeutic strategies. In the current phase of this R01 grant, we have shown that CD40L-matured dendritic cells (DCs) loaded with HIV-I proteins, peptides or HIV-1 infected apoptotic cells, serve as potent immunogens for activation of memory and primary anti- HIV-1 CD8 ? and CD4 + T cells. We hypothesize that the inherent nafve repertoire of CD8 ? T cells present prior to HIV-1 infection is sufficiently broad to recognize infecting viruses, as well as the variants of the CTL epitopes that evolve over the course of infection. Therefore, in Aim 1 we propose to test primary CD8 ? T cell reactivity in samples obtained prior to infection for recognition of infecting, autologous viruses as well as variants of the epitopes recognized during early infection using autologous HIV-1 infected apoptotic bodies.
In Aim 2, we will characterize sequences of the infecting viruses and the later- evolving variants of epitopes recognized during early infection.
In Aim 3, we will assess the antigen processing mechanisms using DC live cell imaging and expression of markers involved in antigen processing pathways. Since the reconstitution of anti-HIV-1 responses following HAART has a number of similarities to the development of anti-HIV-1 responses following infection, characterization of pre-infection nafve T cell responses will help formulate model strategies to enhance immune responses following HAART. We propose that this DC-apoptotic cell model may be antigenic forms of HIV-1 and can be a vehicle for therapeutic

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI041870-16
Application #
8290399
Study Section
Special Emphasis Panel (NSS)
Program Officer
Bridges, Sandra H
Project Start
1997-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
16
Fiscal Year
2012
Total Cost
$334,092
Indirect Cost
$113,569
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Huang, Xiao-Li; Fan, Zheng; Borowski, LuAnn et al. (2010) Dendritic cells reveal a broad range of MHC class I epitopes for HIV-1 in persons with suppressed viral load on antiretroviral therapy. PLoS One 5:e12936

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