Control of HIV-1 infection in chronically infected patients has been revolutionized by highly active antiretroviral therapy (HAART). However, long term HAART is toxic and there is incomplete recovery of anti-HIV-1 T cell function;removal of HAART usually also results in rapid increases in viral load. Thus, we postulate that immunotherapy specifically directed to autologous virus can lead to adequate control of residual HIV-1 infection during HAART. We hypothesize that dendritic cells (DCs) loaded with apoptotic, autologous cells that are infected with autologous HIV-1 can serve as potent immunogens for activation of both CD8[+] and CD4[+] T cells specific for a broad range of autologous HIV-1 antigens. This is based on our recent findings that DCs loaded with HIV-1 infected, apoptotic cells induce CD8[+] and CD4[+] T cell responses specific for HIV-1 in vitro. To further refine this model, we propose to expand our preclinical studies by comparing the immunogenicity and the breadth of antigen specificity induced ex vivo by DCs loaded with apoptotic cells infected with autologous HIV-1 and DCs matured by different cytokine milieus. We will use this ex vivo model for determining the safety and immunogenicity of ex vivo loaded, autologous DCs as an HIV-1 immunogen in HIV-1 infected adults on HAART in a phase I clinical trial. Finally, we propose to monitor the breadth of CD8[+] and CD4[+] T cell responses to autologous HIV-1 and characterize viral evolutionary changes before and after ex vivo immunization. This DC-apoptotic cell model may be an ideal immunogen in that it contains all forms of HIV-1 proteins and can be used as a vehicle for therapeutic immunization with autologous virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI055794-06
Application #
8214997
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
6
Fiscal Year
2011
Total Cost
$32,920
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Macatangay, Bernard Jc; Rinaldo, Charles R (2010) Regulatory T cells in HIV immunotherapy. HIV Ther 4:639-647
Macatangay, Bernard J C; Szajnik, Marta E; Whiteside, Theresa L et al. (2010) Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS One 5:e9852
Whiteside, Theresa L; Piazza, Paolo; Reiter, Amanda et al. (2009) Production of a dendritic cell-based vaccine containing inactivated autologous virus for therapy of patients with chronic human immunodeficiency virus type 1 infection. Clin Vaccine Immunol 16:233-40