Abstract
BackgroundWe developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses.MethodsPBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells.ResultsThe protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined.ConclusionsMDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment.Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829, posted November 11th, 2016)
Highlights
The onset of HIV-1 infection induces a robust immune response by the host [1, 2]
We compared the viability of DCs differentiated after thawing of frozen PBMCs to that of DCs frozen after isolation
The present study shows the feasibility of using a personalized Gag-based Monocyte-Derived Dendritic-cell Therapy (MDDCT) to increase the adaptive immune response against HIV in patients undergoing suppressive antiretroviral treatment (ART) for prolonged periods
Summary
The onset of HIV-1 infection induces a robust immune response by the host [1, 2]. this response does not typically lead to immunological control of the infection, as shown by the rapid rebound of viremia after interruption of antiretroviral treatment (ART) [3,4,5,6,7]. DCs can migrate to lymph nodes and other HIV-1 sanctuaries and, once activated, produce interleukins such as IL-12, IL-15, and IL-18, promoting a potent cytotoxic T-cell response necessary for the elimination of infected cells. Due to these characteristics, therapy approaches based on DCs have been proposed and tested to modulate the host’s immune response to HIV-1 infection [3, 9,10,11,12,13,14,15,16,17,18,19,20]. We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses
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