Abstract
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.
Highlights
Systems biology approaches applied to immunology and vaccinology aim at analyzing the whole data available from various high throughput technologies to better understand and predict diseases and mechanisms of interventions [1,2,3]
These studies of changes in gene expression of components of the innate immune system help to identify relationships between various pathways involved in responses to vaccines [15, 16] and may contribute to understand variations in vaccine responses according to individual characteristics such as the age [17], sex [6], or seasons [18]
By taking advantage of both blood and cellular analyses, a longitudinal study design and the comparison between a pre- and post antiretroviral interruption (ATI) period, we were able to demonstrate an association between the mobilization of inflammatory pathways, the magnitude of vaccine elicited HIV cellular responses and the viral dynamics after ATI after experimental therapeutic DCbased vaccination in HIV-infected patients
Summary
Systems biology approaches applied to immunology and vaccinology aim at analyzing the whole data available from various high throughput technologies to better understand and predict diseases and mechanisms of interventions [1,2,3]. In vaccinology, these approaches have been successfully used in several applications such as yellow fever [4], influenza [5,6,7,8,9], malaria [10], pneumococcus and meningococcus [11, 12], and HIV vaccines [13] to identify gene signatures associated with vaccine responses. There is a recent trend toward comparing the signatures of various vaccines to distinguish common and specific pathways modulated by each vaccine [11, 12]
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