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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Program Officer
Bridges, Sandra H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Balan, Sreekumar; Arnold-Schrauf, Catharina; Abbas, Abdenour et al. (2018) Large-Scale Human Dendritic Cell Differentiation Revealing Notch-Dependent Lineage Bifurcation and Heterogeneity. Cell Rep 24:1902-1915.e6
Balan, Sreekumar; Finnigan, John; Bhardwaj, Nina (2017) Dendritic Cell Strategies for Eliciting Mutation-Derived Tumor Antigen Responses in Patients. Cancer J 23:131-137
Sabado, Rachel L; Balan, Sreekumar; Bhardwaj, Nina (2017) Dendritic cell-based immunotherapy. Cell Res 27:74-95
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
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
Gonzalez-Gugel, Elena; Saxena, Mansi; Bhardwaj, Nina (2016) Modulation of innate immunity in the tumor microenvironment. Cancer Immunol Immunother 65:1261-8
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
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

Showing the most recent 10 out of 67 publications