Amanda Cobb

Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load.

Efforts aimed at restoring robust immune responses limiting human immunodeficiency virus (HIV)‐1 replication therapeutically are warranted. We report that vaccination with dendritic cells generated ex vivo and loaded with HIV lipopeptides in patients (n = 19) on antiretroviral therapy was well tolerated and immunogenic. Vaccination increased: (i) the breadth of the immune response from 1 (1–3) to 4 (2–5) peptide‐pool responses/patient (p = 0.009); (ii) the frequency of functional T cells (producing at least two cytokines among IFN‐γ, TNF‐α, and IL‐2) from 0.026 to 0.32% (p = 0.002) and from 0.26 to 0.35% (p = 0.005) for CD4+ and CD8+ T cells, respectively; and (iii) the breadth of cytokines secreted by PBMCs upon antigen exposure, including IL‐2, IFN‐γ, IL‐21, IL‐17, and IL‐13. Fifty percent of patients experienced a maximum of viral load (VL) 1 log10 lower than the other half following antiretroviral treatment interruption. An inverse correlation was found between the maximum of VL and the frequency of polyfunctional CD4+ T cells (p = 0.007), production of IL‐2 (p = 0.006), IFN‐γ (p = 0.01), IL‐21 (p = 0.006), and IL‐13 (p = 0.001). These results suggest an association between vaccine responses and a better control of viral replication. These findings will help in the development of strategies for a functional cure for HIV infection.

Development of a HIV-1 lipopeptide antigen pulsed therapeutic dendritic cell vaccine

In the search for a therapeutic HIV-1 vaccine, we describe herein the development of a monocyte-derived dendritic cell (DC) vaccine loaded with a mixture of HIV-1-antigen lipopeptides (ANRS HIV-LIPO-5 Vaccine). LIPO-5 is comprised of five HIV-1-antigen peptides (Gag(17-35), Gag(253-284), Nef(66-97), Nef(116-145), and Pol(325-355)), each covalently linked to a palmitoyl-lysylamide moiety. Monocytes enriched from HIV-1-infected highly active antiretroviral therapy (HAART)-treated patients were cultured for three days with granulocyte-macrophage colony-stimulating factor and alpha-interferon. At day 2, the DCs were loaded with ANRS HIV-LIPO-5 vaccine, activated with lipopolysaccharide, harvested at day 3 and frozen. Flow cytometry analysis of thawed DC vaccines showed expression of DC differentiation markers: CD1b/c, CD14, HLA-DR, CD11c, co-stimulatory molecule CD80 and DC maturation marker CD83. DCs were capable of eliciting an HIV-1-antigen-specific response, as measured by expansion of autologous CD4(+) and CD8(+) T-cells. The expanded T-cells secreted gamma-IFN and interleukin (IL)-13, but not IL-10. The safety and immunogenicity of this DC vaccine are being evaluated in a Phase I/II clinical trial in chronically HIV-1-infected patients on HAART (clinicaltrials.gov identifier: NCT00796770).

P19-45. Development of a therapeutic HIV vaccine comprised of autologous dendritic cells loaded with a mixture of lipopeptide HIV antigens

Background Clinical trials have shown that dendritic cell (DC)-based vaccines can induce antigen-specific immune responses as well as clinical responses in patients with stage IV cancer. In this study, a monocyte-derived DC vaccine pulsed with HIV antigen lipopeptides (LIPO5) was developed in preparation for a pilot vaccine clinical trial (DALIA) aimed at boosting the cellular immune response in chronic HIV infected patients on highly-active antiretroviral therapy (HAART).

P17-04. Targeting HIV peptides to human dendritic cells via CD40 elicits expansion of multi-epitope polyfunctional CD4+ and CD8+ T cells in HIV patients

Background Targeting Dendritic Cells (DCs) with anti-DC receptor antibody-antigen fusion proteins represents a novel approach to vaccine development. In mouse models, these innovative vaccines induce enhanced cellular, humoral, or mixed immune responses. Targeting antigens to particular DC subsets can lead to distinct immune outcomes but the consequence of targeting antigen via different receptors on the same DC is not well-studied.

P16-49. Broad types of cytokines secreted by Gag-specific T cells from HIV infected patients on HAART

Background Previously described highly immunogenic epitopes from Gag are able to stimulate Th1/CTL cells. This response is essential for controlling progression of HIV infection. Techniques like IFN-γ-ELISPOT and IFN-γ intracellular staining are currently the standard methods to define antigen-specific immune responses. A recent method, the Luminex analysis allows the identification of responses characteristic of T cell subtypes through the secretion of not only IFN-γ but other key cytokines (IL-5, IL-13, IL-10, IL-21 and IL-17).

P16-29. HIV Nef-specific T cells: Th1/CTL, Th2 and Th17 responses

Background Identification of promiscuous antigenic regions is crucial for the design of an epitope-based vaccine. Still, the quality of the responses has been under estimated in most cases when only IFN-γ is used to measure anti-HIV cellular immunity. Luminex multiplexing system allows the identification of T cell responses characteristic of T cell subtypes through their secretion of not only Th1/CTL but other important sets of cytokines, including IL-5, Il-10, Il13, IL-21 and IL-17.