Although the institution of antiretroviral therapy (ART) has reduced morbidity and mortality from HIV infection, immune reconstitution is incomplete, virus persists in tissue reservoirs and rebound viremia occurs when treatment is halted. Recent findings that intermittent compliance with drug therapy can stimulate T cell responses has led to the concept that low-level antigenic stimulation through re-exposure to virus, or boosting of T cell responses via immunization, may facilitate control of viral replication as an adjunct to ART. An effective way to generate human CD4+ and CD8+ T cell responses is by presenting antigens on dendritic cells (DCs), a system of antigen presenting cells (APCs) that stimulate innate and acquired immune responses. DCs pulsed with live or chemically inactivated (Aldrithiol2 treated) HIV or SIV (simian immunodeficiency virus), efficiently induce HIV-specific CD4+ and CD8+ T cell responses from human cells in vitro. Aldrithiol2 (AT2) inactivates HIV infectivity without affecting the conformational and functional integrity of virion surface proteins. DCs pulsed with AT2 inactivated SIV induced long-term control of viremia in Chinese rhesus macaques chronically infected with SIVmac251. Furthermore, we have established the safety and immunogenicity of DCs in healthy individuals and more recently in HIV+ individuals. Based on these findings, we will determine whether DCs pulsed with AT2 inactivated-HIV induce therapeutic immune responses in a cohort of chronically infected HIV+ individuals.
The specific aims are to: (1) optimize the capture, processing and presentation of AT2 treated HIV by human DCs in vitro, as a prelude to clinical studies? (2) develop the methodology required to prepare sterile AT2 inactivated autologous HIV from patients monocytes on a level which meets regulatory requirements, and (3) to establish the safety and immunogenicity of DCs pulsed with autologous AT2 inactivated HIV in an ART suppressed, chronically infected HIV+ cohort. These studies will help determine whether non-replicating HIV, when delivered on DCs, induces durable CD4 and CD8 responses which facilitate control of viral replication, even after termination of ART.

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 #
3R37AI044628-16S1
Application #
8744626
Study Section
Program Officer
Bridges, Sandra H
Project Start
2013-12-19
Project End
2015-12-18
Budget Start
2013-12-19
Budget End
2015-12-18
Support Year
16
Fiscal Year
2014
Total Cost
$221,216
Indirect Cost
$90,705
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
O'Brien, Meagan; Manches, Olivier; Wilen, Craig et al. (2016) CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells. PLoS Pathog 12:e1005553
Fernandez, Melissa Victoria; Miller, Elizabeth; Krammer, Florian et al. (2016) Ion efflux and influenza infection trigger NLRP3 inflammasome signaling in human dendritic cells. J Leukoc Biol 99:723-34
Miller, Elizabeth; Spadaccia, Meredith; Sabado, Rachel et al. (2015) Autologous aldrithiol-2-inactivated HIV-1 combined with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose as a vaccine platform for therapeutic dendritic cell immunotherapy. Vaccine 33:388-95
Norton, T D; Miller, E A; Bhardwaj, N et al. (2015) Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro. Gene Ther 22:227-36
Miller, Elizabeth A; Gopal, Ramya; Valdes, Vanessa et al. (2015) Soluble CD40 ligand contributes to dendritic cell-mediated T-cell dysfunction in HIV-1 infection. AIDS 29:1287-96
Miller, Elizabeth A; Spadaccia, Meredith R; Norton, Thomas et al. (2015) Attenuated Listeria monocytogenes vectors overcome suppressive plasma factors during HIV infection to stimulate myeloid dendritic cells to promote adaptive immunity and reactivation of latent virus. AIDS Res Hum Retroviruses 31:127-36
Manches, Olivier; Frleta, Davor; Bhardwaj, Nina (2014) Dendritic cells in progression and pathology of HIV infection. Trends Immunol 35:114-22
Bloch, Nicolin; O'Brien, Meagan; Norton, Thomas D et al. (2014) HIV type 1 infection of plasmacytoid and myeloid dendritic cells is restricted by high levels of SAMHD1 and cannot be counteracted by Vpx. AIDS Res Hum Retroviruses 30:195-203
Sabado, Rachel Lubong; Miller, Elizabeth; Spadaccia, Meredith et al. (2013) Preparation of tumor antigen-loaded mature dendritic cells for immunotherapy. J Vis Exp :
Miller, Elizabeth; Bhardwaj, Nina (2013) A bloody mess: dendritic cells use hemophagocytosis to regulate viral inflammation. Immunity 39:429-31

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