Dendritic cell immunotherapy followed by cART interruption during HIV-1 infection induces plasma protein markers of cellular immunity and neutrophil recruitment.

Henk-Jan Van Den Ham,Arno C Andeweg,Albert D M E Osterhaus,Sabine Bahn,Jason D Cooper,Jakub Tomasik,Rob A Gruters,Joeri L Aerts,On Behalf Of The Dc-Trn Trial Investigators

doi:10.1371/journal.pone.0192278

Abstract

ObjectivesTo characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level.DesignAn autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls.MethodsPlasma marker (‘analyte’) levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression.ResultsPlasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands.ConclusionsChronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC-vaccination in the setting of HIV-infection.

Highlights

Chronic HIV infection is characterized by profound changes in immune function that, if left untreated, will result in AIDS
We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off combined antiretroviral treatment (cART) after dendritic cell (DC) vaccination
Chronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption

Summary

Introduction

Chronic HIV infection is characterized by profound changes in immune function that, if left untreated, will result in AIDS. Many therapeutic HIV vaccination studies have been conducted, some with encouraging results [7,8] as demonstrated by a reduction of plasma viral load (lower set point) or a prolonged time of therapy interruption [9]. In these therapeutic vaccination studies, a range of clinical and laboratory parameters was assessed to monitor vaccine safety, but no classical correlates of vaccine efficacy could be identified to guide generation vaccine trials. Other readouts have been used to assess the effect of vaccination, including a decrease of the viral set point after therapy [8]

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