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Front. Immunol. | doi: 10.3389/fimmu.2019.00874

Gene expression signatures associated with immune and virological responses to therapeutic vaccination with Dendritic Cells in HIV-infected individuals

 Rodolphe Thiebaut1*,  Boris Hejblum1, Hakim Hocini2,  Henri Bonnabau1,  Jason Skinner3, Monica Montes3, Christine Lacabaratz2, Laura Richert1, Karolina Palucka3,  Jacques Banchereau3 and  Yves Levy2
  • 1Université de Bordeaux, France
  • 2INSERM Délégation Paris 12, France
  • 3Baylor Institute for Immunology Research, Baylor University Medical Center, United States

The goal of HIV therapeutic vaccination is to induce HIV-specific immune response able to control HIV replication. We previously reported that vaccination with ex vivo generated Dendritic Cells (DC) loaded with HIV-lipopeptides in HIV-infected patients (n=19) on antiretroviral therapy (ART) was well tolerated and immunogenic. Vaccine-elicited HIV-specific T cell responses were associated with improved control of viral replication following antiretroviral interruption (ATI from w24 to w48). We show an inverse relationship between HIV-specific responses (production of IL-2, IL-13, IL-21, IFN-g, CD4 polyfunctionality, i.e. production of at least two cytokines) and the peak of viral load during ATI. Here we have performed an integrative systems vaccinology analysis including: i) post vaccination (w16) immune responses assessed by cytometry, cytokine secretion and Interferon-γ ELISPOT assays; ii) whole blood and cellular gene expression measured during vaccination and iii) viral parameters following ATI, with the objective to disentangle the relationships between these markers and to identify vaccine signatures. During vaccination, 69 gene expression modules out of 260 varied significantly including (by order of significance) modules related to inflammation (Chaussabel Modules M3.2, M4.13, M4.6, M5.7, M7.1, M4.2), plasma cells (M4.11) and T cells (M4.1, 4.15). Cellular immune responses were positively correlated to genes belonging to T cell functional modules (M4.1, M4.15) at w16 and negatively correlated to genes belonging to inflammation modules (M7.1, M5.7, M3.2, M4.13, M4.2). More specifically, we show that prolonged increased abundance of inflammatory gene pathways related to toll-like receptor signaling (especially TLR4) are associated with both lower vaccine immune responses and control of viral replication post ATI. Further comparison of DC vaccine gene signatures with previously reported non-HIV vaccine signatures, such as flu and pneumococcal vaccines, revealed common pathways across vaccines. Overall, these results show that too long duration and too high intensity of vaccine inflammatory responses hamper the magnitude of effector responses.

Keywords: dendritic cell, HIV, antiretroviral therapy interruption, Therapeutic vaccine, Gene Expression, Systems Biology

Received: 22 May 2018; Accepted: 05 Apr 2019.

Edited by:

José Mordoh, Leloir Institute Foundation (FIL), Argentina

Reviewed by:

Sampa Santra, Beth Israel Deaconess Medical Center, Harvard Medical School, United States
Petronela Ancuta, Université de Montréal, Canada  

Copyright: © 2019 Thiebaut, Hejblum, Hocini, Bonnabau, Skinner, Montes, Lacabaratz, Richert, Palucka, Banchereau and Levy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Rodolphe Thiebaut, Université de Bordeaux, Bordeaux, France, rodolphe.thiebaut@u-bordeaux.fr