The long-term efficacy of combination anti-retroviral 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-1 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 naive 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 naive T cell responses will help formulate model strategies to enhance immune responses following HAART. We propose that this DC-apoptotic cell model may be an ideal immunogen that contains all antigenic forms of HIV-1 and can be a vehicle for therapeutic immunization.

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 #
5R37AI041870-09
Application #
6908134
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Bridges, Sandra H
Project Start
1997-08-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
9
Fiscal Year
2005
Total Cost
$334,125
Indirect Cost
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
Smith, Kellie N; Mailliard, Robbie B; Piazza, Paolo A et al. (2016) Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells. MBio 7:
Macatangay, Bernard J C; Riddler, Sharon A; Wheeler, Nicole D et al. (2016) Therapeutic Vaccination With Dendritic Cells Loaded With Autologous HIV Type 1-Infected Apoptotic Cells. J Infect Dis 213:1400-9
Zaccard, C R; Rinaldo, C R; Mailliard, R B (2016) Linked in: immunologic membrane nanotube networks. J Leukoc Biol 100:81-94
Smith, Kellie N; Mailliard, Robbie B; Rinaldo, Charles R (2015) Programming T cell Killers for an HIV Cure: Teach the New Dogs New Tricks and Let the Sleeping Dogs Lie. For Immunopathol Dis Therap 6:67-77
Macatangay, Bernard J C; Rinaldo, Charles R (2015) Preserving HIV-specific T cell responses: does timing of antiretroviral therapy help? Curr Opin HIV AIDS 10:55-60
Zaccard, Colleen R; Watkins, Simon C; Kalinski, Pawel et al. (2015) CD40L induces functional tunneling nanotube networks exclusively in dendritic cells programmed by mediators of type 1 immunity. J Immunol 194:1047-56
Smith, Kellie N; Mailliard, Robbie B; Larsen, Brendan B et al. (2014) Dendritic cells restore CD8+ T cell reactivity to autologous HIV-1. J Virol 88:9976-90
Zaccard, Colleen R; Watkins, Simon C; Ayyavoo, Velpandi et al. (2014) HIV's ticket to ride: Cytotoxic T-lymphocyte-activated dendritic cells exploited for virus intercellular transfer. AIDS Res Hum Retroviruses 30:1023-4
Melhem, Nada M; Smith, Kellie N; Huang, Xiao-Li et al. (2014) The impact of viral evolution and frequency of variant epitopes on primary and memory human immunodeficiency virus type 1-specific CD8? T cell responses. Virology 450-451:34-48
McKinnon, John E; Mailliard, Robbie B; Swindells, Susan et al. (2014) Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201). PLoS One 9:e95524

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